BackgroundCough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough.Study Design and MethodsA review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms.ResultsWe describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance.InterpretationThis is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management. Cough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms. We describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance. This is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management. This is the second paper in a two-part update on global physiology and pathophysiology of cough in the 2006 American College of Chest Physicians (CHEST) cough guidelines.1McCool F.D. Global physiology and pathophysiology of cough: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 48s-53sAbstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Part one of this update summarized the motor and sensory traits of cough, common presenting descriptive characteristics, physiology of mechanics of cough, how cough is assessed, and where available, how cough characteristics can differ between health and disease. Part two of the update comprises the following applied topics: cough demographics, clinical conditions impacting cough mechanics, and the relationship between cough and airway secretions in airway clearance. In this update, we provide perspective on the physiological and pathophysiological consequences of age on the cough reflex which were not previously addressed in the 2006 guideline. Likewise, the influence of sex on cough in the clinical setting with specific reference to cough hypersensitivity is addressed. As a further extension to the 2006 guideline, the clinical impact of stroke, Parkinson disease, and motor neuron disease on cough mechanics is presented. We carried out a review of the literature using PubMed and MEDLINE from 1951 to 2019 using the search terms shown in Table 1.Table 1Search Terms Used for Reviewing the LiteratureMeSH Search TermsCough AND Aging OR Aged OR ElderlyCough AND EffortCough AND MucusCough AND Gender OR Sex OR Sex factorsCough AND Pathophysiology OR MechanicsCough AND MucinsCough AND NeuromuscularCough AND Airway compressionCough AND Mucociliary OR Mucociliary clearanceCough AND Emphysema OR Decreased airflow OR Flow ratesCough AND Airway collapseCough AND children AND physiology OR reflex OR mechanismCough AND Chronic disease OR Obstructive diseaseMeSH = Medical Subject Headings. Open table in a new tab MeSH = Medical Subject Headings. The previous2Chang A.B. Glomb W.B. Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 260S-283SAbstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar and current3Chang A.B. Oppenheimer J.J. Weinberger M.M. et al.Use of management pathways or algorithms in children with chronic cough: CHEST guideline and expert panel report.Chest. 2017; 151: 875-883Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar CHEST guidelines recommended using pediatric-specific cough pathways when managing children with chronic cough. Reasons for this are many and include key differences between children and adults with respect to the following: common etiologies of chronic cough,4Chang A.B. Oppenheimer J.J. Weinberger M.M. et al.Etiologies of chronic cough in pediatric cohorts: CHEST guideline and expert panel report.Chest. 2017; 152: 607-617Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar assessment of outcomes, the maturational aspects of immunity (eg, innate, humoral, cellular),5Tulic M.K. Fiset P.-O. Manoukian J.J. et al.Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults.Lancet. 2004; 363: 1689-1697Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar and physiological aspects of the respiratory system (eg, airway size, respiratory muscle development) from childhood to adulthood. Specific to the cough reflex, there are however little data in children, despite the increased knowledge regarding cough physiology over the last decade. Nevertheless, because the physiology of the cough pathway is intrinsically linked with the respiratory system (including the expiratory reflex, respiratory control, and the pump mechanism), these maturation aspects of the cough pathway are important. The subsequent section details available data. Although the cough reflex first becomes evident at 1 to 2 months of age and develops with increasing maturity, it is weak in premature infants.6Thach B.T. Maturation of cough and other reflexes that protect the fetal and neonatal airway.Pulm Pharmacol Ther. 2007; 20: 365-370Crossref PubMed Scopus (64) Google Scholar Stimulation of the laryngeal chemoreflex in young infants results in swallowing, apnea, and laryngeal closure.6Thach B.T. Maturation of cough and other reflexes that protect the fetal and neonatal airway.Pulm Pharmacol Ther. 2007; 20: 365-370Crossref PubMed Scopus (64) Google Scholar With maturation, cough becomes an increasingly prominent component of the laryngeal chemoreflex response. Animal work suggests that feeding behavior also influences its maturation where expiration reflex dominates in younger pups while cough was more readily triggered in weaning animals.7Coutier-Marie L. Ioan I. Bonabel C. et al.Maturation of airway defensive reflexes is related to development of feeding behavior during growth in rabbits.Front Physiol. 2017; 8: 64Crossref PubMed Scopus (4) Google Scholar In some people, stimulation of the auricular branch of the vagus nerve can elicit Arnold ear-cough reflex. The reflex is evoked by palpation of the posteroinferior wall, palpation of the anteroinferior wall of the external acoustic meatus (ear canal), or mechanical stimulation of the ear canal with insertion of cotton-tip applicator 3 to 5 mm for 2 to 3 s.8Dicpinigaitis P.V. Kantar A. Enilari O. Paravati F. Prevalence of Arnold nerve reflex in adults and children with chronic cough.Chest. 2018; 153: 675-679Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,9Tekdemir I. Aslan A. Elhan A. A clinico-anatomic study of the auricular branch of the vagus nerve and Arnold's ear-cough reflex.Surg Radiol Anat. 1998; 20: 253-257PubMed Google Scholar Data suggest differences between children and adults with a similar prevalence of the reflex in children with chronic cough and healthy individuals, contrasting the 11-fold higher prevalence in adults with chronic cough compared with healthy adults and those with respiratory disease without cough.8Dicpinigaitis P.V. Kantar A. Enilari O. Paravati F. Prevalence of Arnold nerve reflex in adults and children with chronic cough.Chest. 2018; 153: 675-679Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Exercise modulates the cough reflex. One study examined the capsaicin cough sensitivity and found that exercise reduced cough sensitivity in all healthy adults but only in approximately 80% of healthy children.10Demoulin-Alexikova S. Marchal F. Bonabel C. et al.Down-regulation of cough during exercise is less frequent in healthy children than adults. Role of the development and/or atopy?.Front Physiol. 2017; 8: 304Crossref PubMed Scopus (7) Google Scholar Although the reason for this difference is not known, a higher incidence of personal and familial atopy may be present in children who did not show a reduction in cough during exercise compared with children who did.10Demoulin-Alexikova S. Marchal F. Bonabel C. et al.Down-regulation of cough during exercise is less frequent in healthy children than adults. Role of the development and/or atopy?.Front Physiol. 2017; 8: 304Crossref PubMed Scopus (7) Google Scholar Another aspect in cough-specific physiological maturation influence is the age- and sex-related differences in cough sensitivity. In prepubertal children, cough sensitivity is similar in boys and girls and therefore not influenced by sex. However, heightened cough sensitivity has been documented in postpubertal adolescents and adult women compared with men.11Chang A.B. Gibson P.G. Willis C. et al.Do sex and atopy influence cough outcome measurements in children?.Chest. 2011; 140: 324-330Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Exactly when children's cough reflex becomes fully matured is unknown; however, it likely occurs in postpuberty. The critical windows of exposure in utero and early childhood for health, disease, and even social determinants have long been appreciated.12Pinkerton K.E. Joad J.P. The mammalian respiratory system and critical windows of exposure for children's health.Environ Health Perspect. 2000; 108: 457-462Crossref PubMed Scopus (117) Google Scholar Like other parts of neural development, developmental plasticity for the cough reflex is also likely important with the interplay between the young child with prenatal and/or postnatal environmental conditions.13Ioan I. Poussel M. Coutier L. et al.What is chronic cough in children?.Front Physiol. 2014; 5: 322Crossref PubMed Scopus (10) Google Scholar,14Sekizawa S. Joad J.P. Pinkerton K.E. Bonham A.C. Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates.Toxicol Appl Pharmacol. 2010; 242: 199-208Crossref PubMed Scopus (11) Google Scholar Elegant studies involving primates have shown differential effects of secondhand smoke (SHS) exposure to intrinsic and synaptic excitabilities of the nervous system.14Sekizawa S. Joad J.P. Pinkerton K.E. Bonham A.C. Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates.Toxicol Appl Pharmacol. 2010; 242: 199-208Crossref PubMed Scopus (11) Google Scholar The authors postulated that the "influence of SHS exposure on age-related (in utero, neonatal, infant) and neurophenotype specific changes may be associated with age-specific respiratory problems (e.g. bronchiolitis in infants and asthma in children), for which SHS exposure can increase the risk."14Sekizawa S. Joad J.P. Pinkerton K.E. Bonham A.C. Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates.Toxicol Appl Pharmacol. 2010; 242: 199-208Crossref PubMed Scopus (11) Google Scholar Older adults (≥ 65 years of age) have a higher risk of both acute or chronic cough and impaired coughing compared with younger adult cohorts.15Kang M.-G. Song W.-J. Kim H.-J. et al.Point prevalence and epidemiological characteristics of chronic cough in the general adult population: The Korean National Health and Nutrition Examination Survey 2010-2012.Medicine (Baltimore). 2017; 96e6486Crossref PubMed Scopus (20) Google Scholar The incidence of chronic cough in older adults is relatively high, approaching 10%.16Song W.-J. Morice A.H. Kim M.-H. et al.Cough in the elderly population: relationships with multiple comorbidity.PLoS One. 2013; 8e78081Crossref PubMed Scopus (37) Google Scholar The largest analyses that have focused specifically on cough demographics have included mainly people of Asian descent.15Kang M.-G. Song W.-J. Kim H.-J. et al.Point prevalence and epidemiological characteristics of chronic cough in the general adult population: The Korean National Health and Nutrition Examination Survey 2010-2012.Medicine (Baltimore). 2017; 96e6486Crossref PubMed Scopus (20) Google Scholar,16Song W.-J. Morice A.H. Kim M.-H. et al.Cough in the elderly population: relationships with multiple comorbidity.PLoS One. 2013; 8e78081Crossref PubMed Scopus (37) Google Scholar In a meta-analysis, Song et al17Song W.-J. Chang Y.-S. Faruqi S. et al.The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.Eur Respir J. 2015; 45: 1479-1481Crossref PubMed Scopus (169) Google Scholar presented evidence that chronic cough was more frequent in western countries than in Asia or Africa, but they did not specifically identify older adults in their analyses. In a worldwide study of 10,032 patients presenting with chronic cough, the most common age for presentation with chronic cough was 60 to 69 years of age.18Morice A.H. Jakes A.D. Faruqi S. et al.A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response.Eur Respir J. 2014; 44: 1149-1155Crossref PubMed Scopus (125) Google Scholar Causes of enhanced coughing in this group mirror well-known underlying conditions that cause chronic cough in the general population, with smoking, asthma, and rhinitis being the most common comorbidities.16Song W.-J. Morice A.H. Kim M.-H. et al.Cough in the elderly population: relationships with multiple comorbidity.PLoS One. 2013; 8e78081Crossref PubMed Scopus (37) Google Scholar However, other comorbidities are also prevalent in older adults, including diabetes mellitus and constipation,16Song W.-J. Morice A.H. Kim M.-H. et al.Cough in the elderly population: relationships with multiple comorbidity.PLoS One. 2013; 8e78081Crossref PubMed Scopus (37) Google Scholar and significance of these in the etiology of chronic cough in older adults is not understood. In a report of 1,000 older adult participants in the Korean Longitudinal Study of Health and Aging, the prevalence of depression was approximately 5% and associated with the presence of chronic cough rather than comorbid asthma.19Sohn K.-H. Song W.-J. Kim S.-H. Jang H.-C. Kim K.W. Chang Y.-S. Chronic cough, not asthma, is associated with depression in the elderly: a community-based population analysis in South Korea.Korean J Intern Med. 2019; 34: 1363-1371Crossref PubMed Scopus (5) Google Scholar In a study of Chinese patients with chronic cough attending a specialist clinic, older adults (> 50 years of age) had elevated cough sensitivity to inhaled capsaicin than younger patients. Whether this finding is directly associated with problems of chronic cough reported in older individuals is not certain.20Lai K. Long L. Yi F. et al.Age and sex distribution of Chinese chronic cough patients and their relationship with capsaicin cough sensitivity.Allergy Asthma Immunol Res. 2019; 11: 871-884Crossref PubMed Scopus (12) Google Scholar Impaired cough can occur in older adults and is strongly associated with pathologic states, such as neurologic diseases.21Hammond C.A.S. Goldstein L.B. Cough and aspiration of food and liquids due to oral-pharyngeal dysphagia: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 154S-168SAbstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 22Marik P.E. Kaplan D. Aspiration pneumonia and dysphagia in the elderly.Chest. 2003; 124: 328-336Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar, 23Pitts T. Bolser D. Rosenbek J. Troche M. Sapienza C. Voluntary cough production and swallow dysfunction in Parkinson's disease.Dysphagia. 2008; 23: 297-301Crossref PubMed Scopus (84) Google Scholar, 24Satoru E. Hiroshi S. Akio K. et al.Impaired efficacy of cough in patients with Parkinson disease.Chest. 2003; 124: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar In these conditions, there is a strong association of impaired cough mechanics and cough sensitivity with dysphagia.23Pitts T. Bolser D. Rosenbek J. Troche M. Sapienza C. Voluntary cough production and swallow dysfunction in Parkinson's disease.Dysphagia. 2008; 23: 297-301Crossref PubMed Scopus (84) Google Scholar,25Smith Hammond C.A. Goldstein L.B. Zajac D.J. Gray L. Davenport P.W. Bolser D.C. Assessment of aspiration risk in stroke patients with quantification of voluntary cough.Neurology. 2001; 56: 502-506Crossref PubMed Google Scholar The presence of both dysphagia and impaired coughing has been linked to an increased risk of aspiration pneumonia.21Hammond C.A.S. Goldstein L.B. Cough and aspiration of food and liquids due to oral-pharyngeal dysphagia: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 154S-168SAbstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,22Marik P.E. Kaplan D. Aspiration pneumonia and dysphagia in the elderly.Chest. 2003; 124: 328-336Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar,26Ebihara S. Ebihara T. Kohzuki M. Effect of aging on cough and swallowing reflexes: implications for preventing aspiration pneumonia.Lung. 2012; 190: 29-33Crossref PubMed Scopus (59) Google Scholar,27Ebihara S. Sekiya H. Miyagi M. Ebihara T. Okazaki T. Dysphagia, dystussia, and aspiration pneumonia in elderly people.J Thorac Dis. 2016; 8: 632-639Crossref PubMed Scopus (64) Google Scholar Co-occurrence of these impairments is thought to lead to increased vocal cord penetration and aspiration of pathogen-laden saliva and food materials.21Hammond C.A.S. Goldstein L.B. Cough and aspiration of food and liquids due to oral-pharyngeal dysphagia: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 154S-168SAbstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,26Ebihara S. Ebihara T. Kohzuki M. Effect of aging on cough and swallowing reflexes: implications for preventing aspiration pneumonia.Lung. 2012; 190: 29-33Crossref PubMed Scopus (59) Google Scholar,28Ebihara S. Ebihara T. Cough in the elderly: a novel strategy for preventing aspiration pneumonia.Pulm Pharmacol Ther. 2011; 24: 318-323Crossref PubMed Scopus (26) Google Scholar, 29Pitts T. Troche M. Mann G. Rosenbek J. Okun M.S. Sapienza C. Using voluntary cough to detect penetration and aspiration during oropharyngeal swallowing in patients with Parkinson disease.Chest. 2010; 138: 1426-1431Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 30Smith Hammond C.A. Goldstein L.B. Horner R.D. Gray L. et al.Predicting aspiration in patients with ischemic stroke: comparison of clinical signs and aerodynamic measures of voluntary cough.Chest. 2009; 135: 769-777Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Impaired coughing reduces the ability of the subject to expectorate this pathogen-laden material, thereby increasing exposure of the airway mucosa to colonization.27Ebihara S. Sekiya H. Miyagi M. Ebihara T. Okazaki T. Dysphagia, dystussia, and aspiration pneumonia in elderly people.J Thorac Dis. 2016; 8: 632-639Crossref PubMed Scopus (64) Google Scholar Ebihara et al26Ebihara S. Ebihara T. Kohzuki M. Effect of aging on cough and swallowing reflexes: implications for preventing aspiration pneumonia.Lung. 2012; 190: 29-33Crossref PubMed Scopus (59) Google Scholar have proposed a model in which age-related cognitive decline is associated with the emergence of dysphagia and later dystussia. Further declines lead to loss of ambulation and/or impaired consciousness, silent aspiration, and community-acquired pneumonia. Silent aspiration is the lack of coughing in response to intrusion of material into the larynx and/or lower airways. These investigators have proposed that repeated microaspiration leads to chronic airway inflammation, even in the absence of colonization by pathogens. This airway inflammation could enhance the risk of further dysphagia.26Ebihara S. Ebihara T. Kohzuki M. Effect of aging on cough and swallowing reflexes: implications for preventing aspiration pneumonia.Lung. 2012; 190: 29-33Crossref PubMed Scopus (59) Google Scholar Sex modifies many aspects of cough. Both cough prevalence and cough reflex sensitivity are increased in adult women, and studies from many countries consistently report a preponderance of female patients (approximately two-thirds) presenting to clinics.18Morice A.H. Jakes A.D. Faruqi S. et al.A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response.Eur Respir J. 2014; 44: 1149-1155Crossref PubMed Scopus (125) Google Scholar However, this sex effect is not evident in cough clinics in China.20Lai K. Long L. Yi F. et al.Age and sex distribution of Chinese chronic cough patients and their relationship with capsaicin cough sensitivity.Allergy Asthma Immunol Res. 2019; 11: 871-884Crossref PubMed Scopus (12) Google Scholar Population prevalence studies indicate that chronic cough is more prevalent among nonsmoking adult women than men.31Çolak Y. Nordestgaard B.G. Laursen L.C. Afzal S. Lange P. Dahl M. et al.Risk factors for chronic cough among 14,669 individuals from the general population.Chest. 2017; 152: 563-573Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Among ex-smokers, there is a similar prevalence of cough in men and women. In children, boys experience more cough than girls during the first decade of life, whereas this sex effect reverses after 14 years of age, and adolescent girls report more cough than adolescent boys.32Jurca M. Ramette A. Dogaru C.M. et al.Prevalence of cough throughout childhood: a cohort study.PLoS One. 2017; 12e0177485Crossref PubMed Scopus (16) Google Scholar Cough as a side-effect of angiotensin converting enzyme inhibitor therapy is more common in women than men.33Brugts J.J. Arima H. Remme W. et al.The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease.Int J Cardiol. 2014; 176: 718-723Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Cough hypersensitivity is more prevalent in adult women and can be demonstrated experimentally with an increased cough response to inhaled capsaicin not only among adult women with chronic cough,18Morice A.H. Jakes A.D. 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These include allotussia (cough triggered by nontussive stimuli) and laryngeal paresthesia (somatic sensations experienced without direct stimulation and localized to the laryngeal area).36Hilton E. Marsden P. Thurston A. Kennedy S. Decalmer S. Smith J.A. Clinical features of the urge-to-cough in patients with chronic cough.Respir Med. 2015; 109: 701-707Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar The Arnold nerve reflex, itself a form of allotussia, whereby cough is elicited by minimal mechanical stimulation, is also increased in adult women with chronic cough.8Dicpinigaitis P.V. Kantar A. Enilari O. Paravati F. Prevalence of Arnold nerve reflex in adults and children with chronic cough.Chest. 2018; 153: 675-679Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,37Ryan N.M. Gibson P.G. Birring S.S. 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Clinical features of the urge-to-cough in patients with chronic cough.Respir Med. 2015; 109: 701-707Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Sex may also influence response to treatment for cough, with evidence that women with laryngopharyngeal reflux-associated cough, who respond to treatment with proton pump inhibitors, have delayed time to maximal treatment effect.39Lechien J.R. Huet K. Finck C. et al.Clinical and acoustical voice quality evolutions throughout empirical treatment for laryngopharyngeal reflux disease according to gender: a preliminary study.Folia Phoniatr Logop. 2020; 72: 257-266Crossref PubMed Scopus (5) Google Scholar In contrast, sex is not observed to modify response to neuromodulator therapy (eg, amitriptyline, gabapentin) used to treat chronic cough.40Ryan M.A. Cohen S.M. Long-term follow-up of amitriptyline treatment for idiopathic cough.Laryngoscope. 2016; 126: 2758-2763Crossref PubMed Scopus (18) Google Scholar, 41Ryan N.M. 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Therefore, in patients with endotracheal tubes in place, a tracheostomy need not be performed to just improve cough effectiveness.1McCool F.D. Global physiology and pathophysiology of cough: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 48s-53sAbstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Cough efficacy is determined by several factors, including the lung volume at cough initiation, compression phase duration and development of tracheal pressure, coug

Objectives: Obstructive sleep apnea (OSA) is associated with treatment-resistant hypertension (RHTN) and may contribute to refractory hypertension (RfHTN). The objective of the current study was to test the hypothesis that patients with RfHTN have more severe OSA compared with patients with controlled RHTN. Methods: Patients (n = 187) referred to the University of Alabama at Birmingham Hypertension Clinic for evaluation and treatment of RHTN, defined as uncontrolled blood pressure (BP) (SBP > 130mmHg or DBP > 80 mmHg) despite the use of at least three antihypertensive medications including a diuretic, were enrolled following completion of at least three follow-up clinic visits. RfHTN was defined as uncontrolled high BP despite treatment with five or more antihypertensive agents of different classes, including a long-acting thiazide-type diuretic and a mineralocorticoid receptor antagonist. Following enrollment, all patients (n = 130) completed 24-h ambulatory BP measurement and overnight diagnostic polysomnography during normal nightly use of continuous positive airway pressure. Analyses examined the severity of OSA and related sleep characteristics among patients with RfHTN versus controlled RHTN. Results: Of the 130 evaluated patients, 37 (28.5%) had RfHTN and 93 (71.5%) had controlled RHTN. In unadjusted analyses, there was not a significant difference in OSA severity, oxygen saturation, or hypoxemia time in patients with RfHTN versus controlled RHTN (P>0.05). Men with RfHTN had more severe OSA compared with men with controlled RHTN (P = 0.044). In adjusted analyses, OSA severity was associated with sex (P<0.0001), but not hypertension phenotype (P = 0.17). Conclusion: The severity of OSA may contribute to RfHTN status in men but not women.

BACKGROUND: Patients commonly present to primary care services with upper and lower respiratory tract infections, and guidelines to help physicians investigate and treat acute cough due to suspected pneumonia and influenza are needed. METHODS: A systematic search was carried out with eight patient, intervention, comparison, outcome questions related to acute cough due to suspected pneumonia or influenza. RESULTS: There was a lack of randomized controlled trials in the setting of outpatients presenting with acute cough due to suspected pneumonia or influenza who were not hospitalized. Both clinical suggestions and research recommendations were made on the evidence available and CHEST Expert Cough Panel advice. CONCLUSIONS: For outpatient adults with acute cough due to suspected pneumonia, we suggest the following clinical symptoms and signs are suggestive of pneumonia: cough; dyspnea; pleural pain; sweating, fevers, or shivers; aches and pains; temperature >= 38 degrees C; tachypnea; and new and localizing chest examination signs. Those suspected of having pneumonia should undergo chest radiography to improve diagnostic accuracy. Although the measurement of C-reactive protein levels strengthens both the diagnosis and exclusion of pneumonia, there was no added benefit of measuring procalcitonin levels in this setting. We suggest that there is no need for routine microbiological testing. We suggest the use of empiric antibiotics according to local and national guidelines when pneumonia is suspected in settings in which imaging cannot be performed. Where there is no clinical or radiographic evidence of pneumonia, we do not suggest the routine use of antibiotics. There is insufficient evidence to make recommendations for or against specific nonantibiotic, symptomatic therapies. Finally, for outpatient adults with acute cough and suspected influenza, we suggest that initiating antiviral treatment (according to Centers for Disease Control and Prevention advice) within 48 hours of symptoms could be associated with decreased antibiotic use and hospitalization and improved outcomes.

Introduction: Masked uncontrolled hypertension (MUCH) is defined as controlled automated office blood pressure (AOBP) in clinic, but uncontrolled out-of-clinic BP by 24-hr ambulatory blood pressure monitoring (ABPM). Prior studies indicate that the prevalence of masked hypertension in patients with newly diagnosed obstructive sleep apnea (OSA) is nearly 30%. In addition, patients with OSA have a higher prevalence of masked hypertension than patients without OSA. Aim: Prospective determination of the prevalence and severity of OSA in patients with MUCH. Methods: In this prospective evaluation, 167 treated hypertensive patients were recruited from the University of Alabama at Birmingham Hypertension Clinic after having controlled BP at three or more clinic visits. All patients were evaluated by AOBP with the BpTRU device, ABPM, and diagnostic polysomnography (PSG) to determine the presence and severity of OSA based on the apnea-hypopnea index (AHI). Out of 153 who completed ABPM, 58 patients were controlled by AOBP and by ABPM, indicating true controlled hypertension and the remaining 95 patients were controlled by AOBP, but uncontrolled by ABPM, indicative of MUCH. 49 true controlled hypertensive and 69 MUCH patients completed PSG. Results: MUCH patients had a mean AHI of 10.3±13.3 compared to 4.5±10.2 events/hr in true controlled hypertension (p =0.045). Overall, the prevalence of OSA was 48.5% in patients with MUCH compared to 26.5% in true controlled hypertension (p = 0.01). Conclusion: MUCH has significant higher prevalence and severity of OSA compared to true controlled hypertension. These findings suggest that untreated OSA may contribute to the development of MUCH.

Refractory hypertension (rHTN), a unique phenotype of antihypertensive treatment failure, is defined as the persistence of uncontrolled high blood pressure (>140/90 mmHg) despite treatment with 5 or more antihypertensive agents. Controlled resistant hypertension (crHTN) is defined as controlled blood pressure requiring 3 or more medications from different classes, including a diuretic. We have previously reported that patients with rHTN exhibit heightened sympathetic tone when compared with those with crHTN. Therefore, this study sought to investigate sleep as a potential mediating mechanism underlying rHTN. We hypothesized that patients with rHTN would have more severe obstructive sleep apnea (OSA) than patients with crHTN as a contributing factor to their heightened sympathetic tone. Consecutive patients (n=80) from the UAB Hypertension Clinic with either rHTN (n=29) or crHTN (n=51) were evaluated by overnight polysomnography. Multivariate analysis of variance was used to compare sleep characteristics between these two groups of patients. Compared with patients with crHTN, those with rHTN were younger (54.6 ± 9.9 versus 58.1 ± 11.6 years) and more likely to be black (75.9% versus 54.9%) and female (69.0% versus 37.3%). Patients with rHTN had more total sleep time (p=0.017) and more time spent in N2 sleep (p=0.002). There were no other significant differences in sleep architecture, number of awakenings, or time spent awake after sleep onset. Patients with rHTN had a higher sleeping heart rate (p=0.040). There were statistically non-significant trends for patients with rHTN to have a higher mean apnea hypopnea index (AHI), as well as for a larger percentage of these patients to have an AHI>5, although these trends were not statistically significant (p=0.367). These findings indicate that patients with rHTN do not exhibit worse OSA compared with patients with crHTN. Therefore, more severe OSA does not explain the heightened sympathetic tone observed in patients with rHTN. This study was supported by NIH grant R01 HL113004 and grant 15SFRN2390002 from the American Heart Association.

Free AccessSleep StagingAASM Scoring Manual Updates for 2017 (Version 2.4) Richard B. Berry, MD, Rita Brooks, MEd, RST, RPSGT, Charlene Gamaldo, MD, Susan M. Harding, MD, Robin M. Lloyd, MD, Stuart F. Quan, MD, Matthew T. Troester, DO, Bradley V. Vaughn, MD Richard B. Berry, MD Address correspondence to: Richard B. Berry, MD, University of Florida, Box 100225 HSC, Gainesville, FL 32610(352) 262-1575 E-mail Address: [email protected] University of Florida, Gainesville, Florida Search for more papers by this author , Rita Brooks, MEd, RST, RPSGT Capital Health, Hamilton, New Jersey Search for more papers by this author , Charlene Gamaldo, MD Johns Hopkins University, Baltimore, Maryland Search for more papers by this author , Susan M. Harding, MD University of Alabama at Birmingham, Birmingham, Alabama Search for more papers by this author , Robin M. Lloyd, MD Mayo Clinic, Rochester, Minnesota Search for more papers by this author , Stuart F. Quan, MD Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts University of Arizona College of Medicine, Tucson, Arizona Search for more papers by this author , Matthew T. Troester, DO Phoenix Children's Hospital, Phoenix, Arizona Search for more papers by this author , Bradley V. Vaughn, MD University of North Carolina, Chapel Hill, North Carolina Search for more papers by this author Published Online:May 15, 2017https://doi.org/10.5664/jcsm.6576Cited by:547SectionsPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutINTRODUCTIONThe Editorial Board of The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications (AASM Scoring Manual) would like to notify the membership and the sleep community that an update for the AASM Scoring Manual (Version 2.4) was released April 1, 2017.1 All AASM-accredited sleep facilities will be required to implement the new rules in the new version by October 1, 2017. The changes for Version 2.4, which were approved by the AASM Board of Directors, are briefly outlined as follows: A new section on performing calibrations and biocalibrations to document appropriate system response was added to chapter III. Technical and Digital Specifications (Section E).The recommended electrooculography (EOG) electrode positions and figure were updated in Section B in chapter IV. Sleep Staging Rules Part 1: Rules for Adults.A new note was added to rule D.1 in chapter IV. Sleep Staging Rules Part 1: Rules for Adults to clarify when to use the term “Stage R” versus “REM sleep.”The definition of “slow wave activity” in rule D.3 in chapter IV. Sleep Staging Rules Part 1: Rules for Adults, and throughout the manual, was updated for consistency to be > 75 μV.The definition of “atrial fibrillation” was updated in both the glossary and in rule B.6 in chapter VI. Cardiac Rules.Rule B.4 in chapter VII. Movement Rules was revised to remove mention of a “sleep-disordered breathing event.”New notes were added in chapter VIII. Respiratory Rules Part 2: Rules for Children for the scoring of apneas and the scoring of hypopneas. Compared to previous revisions, only a modest number of changes have been made. The major revision is the addition of a standard set of calibrations and biocalibrations to document adequate function of the electroencephalography, EOG, and electromyography electrodes as well as the respiratory sensors at the start and end of a sleep study. Most sleep centers already perform similar calibrations and biocalibrations. The goal of this addition was to standardize the procedure and to improve the quality of sleep recordings in sleep centers not currently performing such procedures. High-quality biocalibrations improve the ability to accurately stage sleep and allow the sleep technologist to troubleshoot problems before the study begins. The electrode locations for the recommended EOG electrodes (E1, E2) have also been slightly modified to conform to what the Editorial Board believes is a more practical location consistent with the current practice in most sleep centers. New respiratory notes were added to the respiratory scoring rules for children to make them more consistent with those in the adult section. A note clarifying use of the term stage R versus REM sleep has been added. Additional changes were also made to improve consistency throughout the manual.Each month the Editorial Board receives numerous inquiries about interpretation of the scoring rules and recommendations for changes in the rules or need for clarification in the wording. The Editorial Board appreciates the many thoughtful questions and suggestions. We are developing an FAQ section for the AASM website for the membership to view previous inquiries and responses. There are some recurring questions for which there are no definitive answers because of a lack of published data. The Editorial Board initiated ongoing meetings with the AASM Inter-scorer Reliability (ISR) gold standard scorers in an effort to understand the challenges involved with applying the current rules to real life tracings. Communication between the ISR gold standard scorers and the Editorial Board is ongoing. The Editorial Board is well aware that revisions may require some additional effort in changing scoring habits developed over many years. Our goal is to make changes only when the perceived benefit is worth the challenges of change.DISCLOSURE STATEMENTDr. Vaughn is a paid author for UptoDate (subject nocturnal events) and Neurobase (variety of sleep and epilepsy subjects), and receives research funding as a co-investigator from Axovant for a REM sleep behavior study. Dr. Quan receives grant funding from the National Institutes of Health, and serves as a consultant to the American Board of Internal Medicine, Nightbalance and Best Doctors. Dr. Gamaldo has an agreement with UpToDate, Inc. and has been paid royalties for her contribution of medical articles for this publication. Dr. Harding receives publishing royalties from UpToDate for revising one editorial card each year. Dr. Harding also receives an honorarium from the American Board of Internal Medicine for MOC process. Drs. Berry, Troester, Lloyd and Ms. Brooks have indicated no financial conflicts of interest.CITATIONBerry RB, Brooks R, Gamaldo C, Harding SM, Lloyd RM, Quan SF, Troester MT, Vaughn BV. AASM scoring manual updates for 2017 (Version 2.4). J Clin Sleep Med. 2017;13(5):665–666.REFERENCE1 Berry RB, Brooks R, Gamaldo CEet al.for the American Academy of Sleep MedicineThe AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical SpecificationsDarien, IL: American Academy of Sleep MedicineVersion 2.4; 2017. 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Diet-induced obesity leads to sleep fragmentation independently of the severity of sleep-disordered breathingKim L, Alexandre C, Pho H, Latremoliere A, Polotsky V and Pham L Journal of Applied Physiology, 10.1152/japplphysiol.00386.2022, Vol. 133, No. 6, (1284-1294), Online publication date: 1-Dec-2022. Exploring cognitive and biological correlates of sleep quality and their potential links with Alzheimer’s disease (ALFASleep project): protocol for an observational studyFauria K, Minguillon C, Knezevic I, Tort-Colet N, Stankeviciute L, Hernández L, Rădoi A, Deulofeu C, Fuentes-Julián S, Turull I, Fusté D, Sánchez-Benavides G, Arenaza-Urquijo E, Suárez-Calvet M, Holst S, Garcés P, Mueggler T, Zetterberg H, Blennow K, Arqueros A, Iranzo Á, Domingo Gispert J, Molinuevo J and Grau-Rivera O BMJ Open, 10.1136/bmjopen-2022-067159, Vol. 12, No. 12, (e067159), Online publication date: 1-Dec-2022. Characteristics of rapid eye movement-related obstructive sleep apnea in Thai patientsSattaratpaijit N, Kulalert P and Wongpradit W Scientific Reports, 10.1038/s41598-022-13382-z, Vol. 12, No. 1, Online publication date: 1-Dec-2022. Evening light environments can be designed to consolidate and increase the duration of REM-sleepVethe D, Drews H, Scott J, Engstrøm M, Heglum H, Grønli J, Wisor J, Sand T, Lydersen S, Kjørstad K, Faaland P, Vestergaard C, Langsrud K and Kallestad H Scientific Reports, 10.1038/s41598-022-12408-w, Vol. 12, No. 1, Online publication date: 1-Dec-2022. Characterising the relationship between sleep stages and associated spectral power in diabetesJohnson J, Curtis F and Durrant S Sleep Epidemiology, 10.1016/j.sleepe.2022.100048, Vol. 2, , (100048), Online publication date: 1-Dec-2022. Effects of severe obstructive sleep apnea on functional prognosis in the acute phase of ischemic stroke and quantitative electroencephalographic markersXu J, Wang J, Wu H, Han F, Wang Q, Jiang Y and Chen R Sleep Medicine, 10.1016/j.sleep.2022.11.035, , Online publication date: 1-Dec-2022. Obstructive sleep apnea is associated with worse cognitive outcomes in acute moderate-to-severe traumatic brain injury: A TBI Model Systems studySteward K, Silva M, Maduri P, Tang X, Wittine L, Dams-O’Connor K and Nakase-Richardson R Sleep Medicine, 10.1016/j.sleep.2022.09.012, Vol. 100, , (454-461), Online publication date: 1-Dec-2022. The correlation between the body shape and otolithic function in patients with obstructive sleep apneaXu X, Gao N, Yu J, Chen B, Chen Z, Ren D, Zhang Q, Fang R and Luo H Sleep Medicine, 10.1016/j.sleep.2022.08.002, Vol. 100, , (112-119), Online publication date: 1-Dec-2022. Prevalence and predictors of sleep‐disordered breathing in chronic heart failure: the SchlaHF‐XT registryArzt M, Oldenburg O, Graml A, Schnepf J, Erdmann E, Teschler H, Schoebel C and Woehrle H ESC Heart Failure, 10.1002/ehf2.14027, Vol. 9, No. 6, (4100-4111), Online publication date: 1-Dec-2022. Associations between risk of Alzheimer's disease and obstructive sleep apnea, intermittent hypoxia, and arousal responses: A pilot studyTsai C, Wu S, Kuan Y, Lin Y, Hsu C, Hsu W, Liu Y, Majumdar A, Stettler M, Yang C, Lee K, Wu D, Lee H, Wu C, Kang J and Liu W Frontiers in Neurology, 10.3389/fneur.2022.1038735, Vol. 13, Age-related changes in fast spindle clustering during non-rapid eye movement sleep and their relevance for memory consolidationChampetier P, André C, Weber F, Rehel S, Ourry V, Laniepce A, Lutz A, Bertran F, Cabé N, Pitel A, Poisnel G, de la Sayette V, Vivien D, Chételat G and Rauchs G Sleep, 10.1093/sleep/zsac282, Effect of exercise interventions for sleep quality in patients with chronic kidney disease: a systematic review and meta-analysisZhang F, Wang H, Huang L, Bai Y, Wang W and Zhang H International Urology and Nephrology, 10.1007/s11255-022-03413-z Reliability of respiratory event detection with continuous positive airway pressure in moderate to severe obstructive sleep apnea — comparison of polysomnography with a device-based analysisRichter M, Schroeder M, Domanski U, Schwaibold M and Nilius G Sleep and Breathing, 10.1007/s11325-022-02740-w A consumer wearable device for tracking sleep respiratory eventsTondo P, Dell’Olio F, Lacedonia D, Sabato R, Leccisotti R, Foschino Barbaro M and Scioscia G Sleep and Breathing, 10.1007/s11325-022-02743-7 Screening for Obstructive Sleep Apnea Risk by Using Machine Learning Approaches and Anthropometric FeaturesTsai C, Huang H, Cheng H, Wang J, Duh P, Hsu W, Stettler M, Kuan Y, Lin Y, Hsu C, Lee K, Kang J, Wu D, Lee H, Wu C, Majumdar A and Liu W Sensors, 10.3390/s22228630, Vol. 22, No. 22, (8630) Effect of Obstructive Sleep Apnea and CPAP Treatment on the Bioavailability of Erythrocyte and Plasma Nitric OxideMochol J, Gawryś J, Szahidewicz-Krupska E, Wiśniewski J, Fortuna P, Rola P, Martynowicz H and Doroszko A International Journal of Environmental Research and Public Health, 10.3390/ijerph192214719, Vol. 19, No. 22, (14719) Elevated beta activity in the nighttime sleep and multiple sleep latency electroencephalograms of chronic insomnia patientsShi Y, Ren R, Lei F, Zhang Y, Vitiello M and Tang X Frontiers in Neuroscience, 10.3389/fnins.2022.1045934, Vol. 16, Subjective Sleep Disruption and Mood Disorders are Associated with the Risk of Chronic Pain in Patients with Obstructive Sleep ApneaLiu L, Li X, Xue P, Wu M, Zeng S, Dai Y and Zhou J Nature and Science of Sleep, 10.2147/NSS.S378246, Vol. Volume 14, , (2023-2032) Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibilityMessineo L, Taranto‐Montemurro L, Calianese N, Gell L, Azarbarzin A, Labarca G, Vena D, Yang H, Wang T, Wellman A and Sands S Respirology, 10.1111/resp.14326, Vol. 27, No. 11, (975-982), Online publication date: 1-Nov-2022. Nasal cannula use during polysomnography in children aged under three with suspected sleep apneaJurado M, Sampol G, Quintana M, Romero O, Cambrodí R, Ferré A and Sampol J Sleep Medicine, 10.1016/j.sleep.2022.07.009, Vol. 99, , (41-48), Online publication date: 1-Nov-2022. Cardiovascular autonomic control during application of different modes of noninvasive ventilation in patients affected by amyotrophic lateral sclerosisCrescimanno G, Greco F, Bertini M and Marrone O Heart & Lung, 10.1016/j.hrtlng.2022.07.007, Vol. 56, , (161-166), Online publication date: 1-Nov-2022. Prevalence of sleep disorders in children with chronic kidney disease: a meta-analysisKang K, Lin M, Chen Y, Lee C, Hsu W and Chang R Pediatric Nephrology, 10.1007/s00467-022-05536-y, Vol. 37, No. 11, (2571-2582), Online publication date: 1-Nov-2022. Inherent regional brain activity changes in male obstructive sleep apnea with mild cognitive impairment: A resting-state magnetic resonance studyShu Y, Liu X, Yu P, Li H, Duan W, Wei Z, Li K, Xie W, Zeng Y and Peng D Frontiers in Aging Neuroscience, 10.3389/fnagi.2022.1022628, Vol. 14, He M, Das P, Hotan G and Purdon P Automatic Segmentation of Sleep Spindles: A Variational Switching State-Space Approach 2022 56th Asilomar Conference on Signals, Systems, and Computers, 10.1109/IEEECONF56349.2022.10052015, 978-1-6654-5906-8, (1301-1305) Repeated automatic sleep scoring based on ear-EEG is a valuable alternative to manually scored polysomnographyKjaer T, Rank M, Hemmsen M, Kidmose P, Mikkelsen K and Lu H PLOS Digital Health, 10.1371/journal.pdig.0000134, Vol. 1, No. 10, (e0000134) Management of Sleep Disturbances in Parkinson’s D

BACKGROUND:Sleep dysfunction is a common and disabling non-motor symptom in Parkinson's disease. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms and subjective sleep in PD, but alternative stimulation parameters to optimize sleep have not been explored. We hypothesized that low frequency STN DBS would improve objective sleep more than conventional settings. METHODS:Twenty PD subjects with STN DBS (18 unilateral, 2 bilateral) underwent 3 non-consecutive nights of polysomnography: DBS off; DBS high frequency (≥130 Hz); and DBS low frequency (60 Hz). Motor symptom tolerability was assessed 30 minutes after resumption of baseline settings the morning following polysomnography. The primary outcome was change in sleep efficiency between high and low frequency nights measured with repeated measures ANOVA. RESULTS:There was no difference in sleep efficiency between nights at high frequency (82.1% (72.6-90.1)) (median (IQR)), low frequency (81.2% (56.2-88.8)), or DBS off (82.8% (75.7-87.4)), p=0.241. Additionally, there was no difference in sleep stage percent, arousals, limb movements, subjective sleep quality, or objective vigilance measures. These outcomes did not change after adjusting for age, sex, disease duration, or side of surgery. No residual adverse motor effects were noted. CONCLUSIONS:Although well tolerated, low frequency STN DBS did not improve objective sleep in PD. Remarkably, objective measures of sleep were not worse with DBS off. These observations point to the potential for adaptive stimulation approaches, through which DBS settings could be optimized during sleep to meet individual needs. Additionally, these changes could preserve battery life without compromising patient outcomes.

In clinical practice, patient characteristics predicting resistant hypertension (RH) include higher blood pressure levels, left ventricular hypertrophy, older age, obesity, chronic kidney disease and diabetes. On the contrary little is known about the role of serum uric acid (SUA) as a risk factor for RH in subjects from general population.580 elderly subjects aged ≥65 years were enrolled in the Risk Of Vascular complications Impact of Genetics in Old people (ROVIGO) study. RH was defined as the failure to maintain blood pressure values below 140 mmHg (systolic) and 90 mmHg (diastolic) despite therapeutic interventions that include appropriate lifestyle measures plus adherence to treatment with full doses of at least three antihypertensive drugs, including a diuretic. RH was confirmed using 24-h ambulatory blood pressure measurement. Hyperuricemic was defined as the subjects having SUA ≥6.8 mg/dl or taking uricosuric drugs. Gender-specific odds ratio (OR) for RH was calculated by logistic regression analysis.The prevalence of RH was 5.7% in the cohort and was higher in women (8.3%) than in men (3.0%, p < 0.05). Independent of chronic kidney disease (OR 3.89, 95% confidence interval 1.49–10.1), hyperuricemia predicted resistant hypertension in women (odds ratio 3.11, 95% confidence intervals 1.06–9.1, p = 0.03) but not in men.In elderly women from the general population, an SUA value of ≥6.8 mg/dl triples the risk of RH. SUA assessment should be recommended to better define the pattern of risk associated with RH.

Free AccessEEGShould the Arousal Scoring Rule Be Changed? Richard B. Berry, MD, Rita Brooks, MEd, RST, RPSGT, Charlene E. Gamaldo, MD, Susan M. Harding, MD, Robin M. Lloyd, MD, Carole L. Marcus, MBBCh, Bradley V. Vaughn, MD Richard B. Berry, MD Address correspondence to: Richard B Berry, MD, FAASM, Division of Pulmonary Medicine, University of Florida Health Science Center, PO Box 100225, Gainesville, FL 32610(352) 376-1611 x6241(352) 379-4155 E-mail Address: [email protected] University of Florida, Gainesville, FL , Rita Brooks, MEd, RST, RPSGT Capital Health System, Trenton NJ , Charlene E. Gamaldo, MD John Hopkins University, Baltimore, MD , Susan M. Harding, MD University of Alabama, Birmingham, AL , Robin M. Lloyd, MD Mayo Clinic College of Medicine, Rochester MN , Carole L. Marcus, MBBCh Children's Hospital of Philadelphia, PA , Bradley V. Vaughn, MD University of North Carolina, Chapel Hill, NC Published Online:April 15, 2015https://doi.org/10.5664/jcsm.4618Cited by:2SectionsPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutINTRODUCTIONThe letter to the editor in this issue of the Journal of Clinical Sleep Medicine from Dr. Zimmerman1 challenges the answer of the 2007 Scoring Manual Steering Committee to a frequently asked question (FAQ M.3) and proposes different rules for arousals associated with events such as hypopneas and periodic limb movements ("caused arousals") versus arousals without obvious cause or association ("spontaneous" arousals). He cites a concern that the requirement for 10 seconds of stable sleep before an arousal will reduce the number of respiratory events that can be scored based on the association with an arousal. He is also concerned about the term "stable" sleep and provides some characteristics he feels are associated with transition from wake to sleep and sleep to wake.The AASM Scoring Manual Editorial Board appreciates the thoughtful comments presented by Dr. Zimmerman. To better understand his comments, the arousal definition, the FAQ M.3 and the response of the 2007 Scoring Manual steering committee will be briefly reviewed.The arousal rule that appears in the most current version of the Scoring Manual2 states: "Score arousal during sleep stages N1, N2, N3, or R if there is an abrupt shift of EEG frequency including alpha, theta and/or frequencies greater than 16 Hz (but not spindles) that lasts at least 3 seconds, with at least 10 seconds of stable sleep preceding the change. Scoring of arousal during REM requires a concurrent increase in submental EMG lasting at least 1 second." The FAQ M.3 and the response from the Steering Committee of the 2007 Scoring Manual are presented below. M.3.In our lab we score arousals associated with PLMs. Since you cannot score arousals unless there is 10 seconds of sleep preceding the arousal, can I score an arousal that is associated with a PLM when there can be as little as 5 seconds since the last PLM with arousal? The answer from the Steering Committee is shown below and is consistent with the current Scoring Manual version 2.1. "The short answer is no, you cannot score arousals with less than 10 seconds of intervening sleep. Members of the Movement Rules and Arousal Rule task forces3,4 were consulted on this question. The Movement Rules perspective was that conceptually it would be possible to have multiple limb-movement related arousals with the minimal interval between limb movements (5 seconds from onset to onset). However, the Arousal Rule perspective is that the scoring of such arousals would be technically quite difficult. Since an arousal must last a minimum of 3 seconds, this would leave only 2 seconds to determine that sleep had resumed. The Steering Committee reviewed both perspectives and determined that the arousal rule should hold and that a minimum of 10 seconds is necessary to reliably determine that the patient has returned to sleep. When periodic limb movements occur with an interval of less than 10 seconds and each is associated with a 3-second arousal, only the first arousal should be scored though both limb movements may be scored. In this scenario, the arousal index and PLM index with arousal but not the Periodic Limb Movement Index would be influenced by not scoring the second 'arousal.'" Although Dr. Zimmerman characterized the response of the Steering Committee as an "edict," both the arousal scoring rule and the answer to M.3 were thoughtfully considered by the Steering Committee after consultation with task forces that did evidence reviews prior to recommending movement and arousal scoring rules. It should be appreciated that scoring rules are meant to cover the majority of patients and the majority of events. There will always be patients and events that require the clinician to provide a reasonable adaptation of the rules. The goal of the Scoring Manual and charge of the Scoring Manual Editorial Board is to present reasonable guidelines for scoring events and provide a standard. The recommendations are based on consensus when there are no clear data.The current Scoring Manual Editorial Board questioned Dr. Michael Bonnet, the first author on the arousal review paper providing evidence for the arousal rule, concerning the requirement of stable sleep.4His answer is as follows: "What we meant by 'stable' sleep referred only to the absence of alpha from the EEG. Our major goal was to assure that the patient had actually fallen asleep or returned to sleep following the preceding arousal as we were concerned with situations where normal young adults have waxing and waning of alpha while falling asleep that we did not think should be scored as a train of arousals." The Scoring Manual Editorial Board agrees that the term "stable" is somewhat ambiguous, as only 10 seconds of EEG/EOG/ EMG consistent with sleep is certainly not stable. In most centers, a 10-second segment that can be considered sleep preceding a putative arousal is the usual interpretation. Given that there have been few questions concerning the meaning of "stable sleep," the Scoring Manual Editorial Board feels that changing the wording is not indicated, and being more specific about requiring certain characteristics of the 10-second interval has the potential to further complicate the scoring of arousals.The Scoring Manual Editorial Board also discussed the issue of respiratory events associated with arousal. In adults, the minimum duration of the change in the hypopnea sensor signal necessary to meet scoring criteria is 10 seconds. Most hypopneas are 15 seconds or longer. The great majority of respiratory events have at least 10 seconds of EEG consistent with sleep that precede the termination of the respiratory event. We would contend that in adults, the requirement of 10 seconds of sleep prior to the termination of the respiratory event disqualifies few putative events. In the example in Figure 1 with a very short duration change in the nasal pressure signal, we believe most would be comfortable with scoring a hypopnea in the absence of a significant desaturation (recommended hypopnea definition).Figure 1: A putative respiratory event with a change in airflow that would qualify the event to be scored as a hypopnea based on association with an arousal. N Press is the nasal pressure channel.Download FigureRegarding PLM associated arousals, the 10-second requirement would affect only individual PLM events that were separated (onset to onset) by more than 5 seconds but where less than 10 seconds of sleep precedes the abrupt shift in EEG frequencies associated with the second leg movement. It would be a rare individual for whom this situation was frequent enough to substantially alter the PLM with arousal index and ultimately change the clinical impression. Indeed, there are no widely supported guidelines for what constitutes an abnormal PLM arousal index.In summary, the Scoring Manual Editorial Board feels that having different rules for "spontaneous," PLM, and respiratory event arousals would further complicate arousal scoring without likely benefit for the majority of patients.The scoring of arousals and interpretation of the arousal index remains an area of controversy. The normal range for the total arousal index increases with age,5 but there are no firm guidelines for what constitutes an abnormal value. As noted previously, what constitutes an abnormal PLM arousal index is also not clearly defined. The relative impact of "spontaneous" versus respiratory and PLM associated arousals likely varies from patient to patient. In the case of "spontaneous" arousals, one would presume that these arousals are associated with some physiological event. We just don't know what the event is or the stimulus that triggered the response of the nervous system. Even noting an association does not necessarily mean causality. Until we are truly measuring the inciting drivers at a more basic neuronal level, we are only looking at shadows of other events. Using advanced EEG analysis techniques or measures of autonomic function, one is often able to detect changes associated with the termination of respiratory events or leg movements that do not meet arousal scoring criteria but which may have physiological significance. However, the clinical significance of these events either in the short term (the restorative nature of sleep) or long term (cardiovascular outcomes) requires further study.3 Hopefully in the future more clinical information will be available to better understand how to identify arousals and understand their significance.In summary, we thank Dr. Zimmerman for his comments. The Scoring Manual Editorial Board has carefully considered his points. In the future, we will continue to elicit comments and review published data that have implications for the scoring rules. The major idea behind the current Scoring Manual is that it can be updated on a regular basis as needed. The rules are not fixed in stone. Up to this point, the major emphasis of revisions has been clarification and simplification of the scoring rules. However, change must be based on consideration of evidence and consensus from a wide group of experts in the field. The impact of a change in definitions on the effort required for scoring and the reliability of scoring must be also be considered.DISCLOSURE STATEMENTThe authors have indicated no financial conflicts of interest.CITATIONBerry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd RM, Marcus CL, Vaughn BV. Should the arousal scoring rule be changed? J Clin Sleep Med 2015;11(4):497–499.REFERENCES1 Zimmerman JStability versus transitional changes in the EEG: from sleep to wakefulness. J Clin Sleep Med; 2015;11:495. LinkGoogle Scholar2 Berry RB, Brooks R, Gamaldo CEet al.for the American Academy of Sleep MedicineAASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications, Version 2.1. Darien, IL: American Academy of Sleep Medicine www.aasmnet.org; 2014. Google Scholar3 Walters AS, Lavigne G, Hening Wet al.The scoring of movements in sleep. J Clin Sleep Med; 2007;3:155-67, 17557425. LinkGoogle Scholar4 Bonnet MH, Doghramji K, Roehrs Tet al.The scoring of arousal in sleep: reliability, validity, and alternatives. J Clin Sleep Med; 2007;3:133-45, 17557423. LinkGoogle Scholar5 Bonnet MH, Arand DLEEG arousal norms by age. J Clin Sleep Med; 2007;3:271-4, 17561594. LinkGoogle Scholar Previous article Next article FiguresReferencesRelatedDetailsCited by A Novel Approach for Sleep Arousal Disorder Detection Based on the Interaction of Physiological Signals and Metaheuristic LearningBadiei A, Meshgini S, Rezaee K and Iqbal N Computational Intelligence and Neuroscience, 10.1155/2023/9379618, Vol. 2023, , (1-18), Online publication date: 13-Jan-2023. Validation of an Automatic Arousal Detection Algorithm for Whole-Night Sleep EEG RecordingsChylinski D, Rudzik F, Coppieters 't Wallant D, Grignard M, Vandeleene N, Van Egroo M, Thiesse L, Solbach S, Maquet P, Phillips C, Vandewalle G, Cajochen C and Muto V Clocks & Sleep, 10.3390/clockssleep2030020, Vol. 2, No. 3, (258-272) Volume 11 • Issue 04 • April 15, 2015ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationMarch 1, 2015Accepted for publicationMarch 1, 2015Published onlineApril 15, 2015 Information© 2015 American Academy of Sleep MedicinePDF download

BACKGROUNDSince the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings.METHODSBy following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel.RESULTSWe recommend for adults, adolescents (≥ 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality-of-Life Questionnaire in adult and adolescent patients and the Parent Cough-Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges.CONCLUSIONSValidated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough. Since the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings. By following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel. We recommend for adults, adolescents (≥ 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality-of-Life Questionnaire in adult and adolescent patients and the Parent Cough-Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges. Validated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough.

V 2.2 of the American Academy of Sleep Medicine (AASM) Manual for the Scoring of Sleep and Associated Events was released on July 1, 2015. The Scoring Manual Editorial Board (previously the Scoring Manual Committee) would like to call attention to the most important changes. As discussed below, there are two new major chapters providing rules for the staging of infant sleep and scoring respiratory events in home sleep apnea testing (HSAT) studies. The new chapters were approved by the AASM Board of Directors to fi ll two obvious gaps in the Scoring Manual. The Scoring Manual Editorial Board would like to emphasize that any changes in the manual are instituted after long deliberation and consultation with area content experts. Version 2.2 of the Scoring Manual, for the fi rst time, includes rules for scoring sleep studies in term infants less than two months of age. This milestone acknowledges the importance of studying sleep across the lifespan, beginning with our youngest patients. The new scoring rules address sleep staging in infants and are based on the classic infant scoring rules of Anders et al.1 Development of these new rules benefi tted from expert consultation from Madeleine Grigg-Damberger, MD, and Mark Scher, MD. One important difference between the current manual and Anders is that sleep is now classifi ed into three stages: REM, NREM and transitional, as compared to the Anders classifi cation of active, quiet and indeterminate sleep. This new classifi cation was based on the physiologic similarities between active and REM sleep, and quiet and NREM sleep. Further, it was realized that young infants have stages of sleep that manifest elements of both REM and NREM sleep; hence, the term “transitional” rather than “indeterminate.” Note that respiratory events in infants should be scored using the standard AASM pediatric scoring criteria. Version 2.2 of the AASM Scoring Manual now also includes scoring rules for adult Home Sleep Apnea Testing (HSAT; chapter IX). The foundation for the development of these rules includes the work of the 2010 AASM Out-of-Center Task Force who developed the SCOPER (Sleep, Cardiovascular, Oximetry, Position, Effort, Respiratory) classifi cation system.2 This classifi cation system systematically evaluated available technology and evidence for diagnosing obstructive sleep apnea using portable devices. These new HSAT scoring rules allow for standardization of scoring and reporting data generated from HSAT AASM Scoring Manual Version 2.2 Updates: New Chapters for Scoring Infant Sleep Staging and Home Sleep Apnea Testing Richard B. Berry, MD1; Charlene E. Gamaldo, MD2; Susan M. Harding, MD3; Rita Brooks, MEd, RST, RPSGT4; Robin M. Lloyd, MD5; Bradley V. Vaughn, MD6; Carole L. Marcus, MBBCh7 1University of Florida, Gainesville, FL; 2Johns Hopkins University, Baltimore, MD; 3University of Alabama, Birmingham, AL; 4Capital Health, Hamilton, NJ; 5Mayo Clinic, Rochester, MN; 6University of North Carolina, Chapel Hill, NC; 7Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA

Free AccessCPAPResistant Hypertension and Untreated Severe Sleep Apnea: Slowly Gaining Insight Susan M. Harding, M.D., F.A.A.S.M. Susan M. Harding, M.D., F.A.A.S.M. Address correspondence to: Susan M. Harding, M.D., Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, 1720 Second Avenue South, THT 422, Birmingham, AL 35294-0006(205) 934-3742(205) 934-3743 E-mail Address: [email protected] University of Alabama at Birmingham, Birmingham, AL Search for more papers by this author Published Online:August 15, 2014https://doi.org/10.5664/jcsm.3948Cited by:2SectionsPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutINTRODUCTIONThirty years ago, Kales et al. noted the potential association between hypertension (HTN) and untreated sleep apnea, with HTN patients having a 30% prevalence of sleep apnea, much higher than in age- and sex-matched controls.1 Then, the Wisconsin Sleep Cohort Study reported that incident HTN was associated with sleep apnea severity, which was further verified by the Zaragoza Sleep Cohort Study in Spain.2,3 The Zaragoza Study also noted that CPAP therapy lowered the rate of incident HTN.3 Other CPAP therapy intervention studies and meta-analyses show that CPAP modestly reduces mean blood pressure (BP) with greater effects noted in patients with higher CPAP adherence, blood pressure measurements, and sleep apnea severity, and in those with daytime sleepiness.4,5 Since, even mild reductions in BP can significantly reduce cardiovascular risk, this finding is significant.In this issue, Dr. Walia and colleagues report their baseline data from the Heart Biomarker Evaluation in Apnea (Heart BEAT) Study, hypothesizing that severe obstructive sleep apnea (OSA) is associated with persistent elevations of BP, despite medical BP management, in patients with high cardiovascular disease (CVD) risk.6 This study examined patients with established stable coronary artery disease, or patients having three or more CVD risk factors. Exclusion criteria included heart failure (EF < 30% or NYHA classification > 2), poorly controlled hypertension or diabetes, prior stroke, and absence of HTN. Participants underwent type III sleep testing, and those with an AHI of 15-50 events/hour were included in the study (unless significant oxygen desaturation or central apnea was present). Results show an association between untreated resistant or difficult-to-treat HTN and OSA severity. Participants with severe OSA, compared to those with moderate OSA, had a higher likelihood of having an elevated BP despite being on ≥ 3 BP medicines, including a diuretic (p = 0.01). Those with severe OSA on multiple BP medications had an odds ratio of 4.1 (95% CI, 1.7-10.2) for having elevated BP, a finding not reproduced in participants not on ≥ 3 antihypertensive medications (including a diuretic).6By definition, resistant HTN consists of patients whose HTN is uncontrolled (BP > 140/90 mm Hg) while on 3 or more medications and occurs in approximately 10% to 15% of all hypertensive patients.7 There is a very high prevalence of OSA in patients with resistant HTN. Logan et al. noted that 96% of men and 65% of women with resistant HTN had AHI ≥ 10 events/hour.8 Our laboratory at the University of Alabama at Birmingham noted that 90% of men and 77% of women with resistant HTN had an AHI ≥ 5 events/hour.9Since even mild reductions in BP significantly reduce cardiovascular risk, patients with resistant HTN and severe OSA may represent a key population to target with aggressive OSA treatment interventions.10 Martinez-Garcia et al. examined 194 patients with resistant HTN having an AHI ≥ 15/hour who were randomized to 12 weeks of CPAP or no CPAP.11 The CPAP group had a 3.1 mm Hg reduction in 24-hour mean BP (p = 0.02) and a 3.2 mm Hg reduction in 24-hour diastolic BP (p = 0.005), without significant changes in 24-hour systolic BP. Also, 35.9% of the CPAP patients had return of the normal nocturnal BP dipper pattern, compared to 21.6% of the patients who did not receive CPAP (p = 0.02; adjusted odds ratio 2.4 [95% CI, 1.2-5.0]).11 These BP outcomes have the potential to significantly reduce the risk of future cardiovascular events.Proposed mechanisms whereby severe OSA impacts BP control include endothelial dysfunction (driven by intermittent hypoxia), increased sympathetic activity, hyperaldosteronism, poor medication adherence, and pharmacokinetic alterations or chronic therapeutic effects from untreated OSA.6There is also the possibility that underlying mechanisms associated with resistant HTN could worsen OSA, so that the relationship could be bi-directional, such that treatment of HTN could improve OSA severity. Aldosterone excess is a common cause of resistant HTN, and 20% of our resistant HTN population has biochemical evidence of primary aldosteronism.12 Interestingly, aldosteronism blockade with spironolactone significantly reduced BP in a small cohort of resistant HTN patients, including in those without biochemical aldosterone excess.13 It is notable that in Walia's cohort, none of the 28 subjects with elevated BP despite an intensive BP regimen were on an aldosterone blocker.6 This could partially explain the correlation between uncontrolled BP, despite an intensive BP regimen and OSA severity. Our laboratory has noted a correlation between plasma aldosterone levels and OSA severity in resistant HTN patients.14 We also observed that spironolactone reduced OSA severity in these patients, despite remaining on a thiazide diuretic.15 Aldosterone excess mediates chronic fluid retention, so our data support the hypothesis that aldosterone-mediated chronic fluid retention could impact (worsen) OSA severity.15 We also noted that increased dietary sodium correlated with OSA severity in patients with resistant HTN and hyperaldosteronism.16 Although this finding needs to be verified in a randomized controlled trial, we postulate that this aldosterone-induced worsening of OSA may be mediated through increased fluid retention in the surrounding soft tissues of the upper airway.Friedman et al. noted that a significant spontaneous fluid shift going from the legs to the neck occurs during sleep time in patients with drug-resistant HTN.17 The AHI strongly correlated with the amount of leg fluid volume displaced.17 Thus, fluid accumulation in the soft tissues of the upper airway in the neck may partly explain the higher OSA severity in patients with resistant HTN.In conclusion, OSA severity correlates with poor BP control in patients with significant cardiovascular risk factors and resistant or difficult-to-control HTN.6 Twelve weeks of CPAP therapy may result in a mild reduction in mean 24-hour BP (3.1 mm Hg) in patients with resistant HTN and an AHI > 15/ hour, which has the potential to reduce CVD risk.9 Mechanisms of the association between resistant HTN and OSA severity are still being elucidated and may be bi-directional.15 Since spironolactone has the potential to improve BP control and AHI in patients with resistant HTN, spironolactone should be considered, along with CPAP therapy, in these patients.15,18,19 Future research will define the best management strategies for OSA patients with resistant hypertension; hopefully it will not take another thirty years.DISCLOSURE STATEMENTDr. Harding is supported by a National Heart, Lung, and Blood Institute Grant, RO1-HL 113004. Dr. Harding has indicated no financial conflicts of interest.CITATIONHarding SM. Resistant hypertension and untreated severe sleep apnea: slowly gaining insight. J Clin Sleep Med 2014;10(8):845-846.REFERENCES1 Kales A, Cadieux RJ, Shaw LCet al.Sleep apnea in a hypertensive population. Lancet; 1984;ii:1005-8, 6149395. CrossrefGoogle Scholar2 Peppard PE, Young T, Palta M, Skatrud JProspective study of the association between sleep-disordered breathing and hypertension. N Engl J Med; 2000;342:1378-84, 10805822. CrossrefGoogle Scholar3 Marin JM, Agusti A, Villar Iet al.Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA; 2012;307:2169-76, 22618924. CrossrefGoogle Scholar4 Bassano LA, Khan Z, Reynolds K, He JEffects of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension; 2007;50:417-23, 17548722. 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Volume 10 • Issue 08 • August 15, 2014ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationJune 1, 2014Accepted for publicationJune 1, 2014Published onlineAugust 15, 2014 Information© 2014 American Academy of Sleep MedicinePDF download