Jeremy E. Orr

Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold

RATIONALE A low respiratory arousal threshold is a physiological trait involved in obstructive sleep apnea (OSA) pathogenesis. Trazodone may increase arousal threshold without compromising upper airway muscles, which should improve OSA. OBJECTIVES We aimed to examine how trazodone alters OSA severity and arousal threshold. We hypothesized that trazodone would increase the arousal threshold and improve the apnea/hypopnea index (AHI) in selected patients with OSA. METHODS Subjects were studied on two separate nights in a randomized crossover design. Fifteen unselected subjects with OSA (AHI ≥ 10/h) underwent a standard polysomnogram plus an epiglottic catheter to measure the arousal threshold. Subjects were studied after receiving trazodone (100 mg) and placebo, with 1 week between conditions. The arousal threshold was calculated as the nadir pressure before electrocortical arousal from approximately 20 spontaneous respiratory events selected randomly. MEASUREMENTS AND MAIN RESULTS Compared with placebo, trazodone resulted in a significant reduction in AHI (38.7 vs. 28.5 events/h, P = 0.041), without worsening oxygen saturation or respiratory event duration. Trazodone was not associated with a significant change in the non-REM arousal threshold (-20.3 vs. -19.3 cm H2O, P = 0.51) compared with placebo. In subgroup analysis, responders to trazodone spent less time in N1 sleep (20.1% placebo vs. 9.0% trazodone, P = 0.052) and had an accompanying reduction in arousal index, whereas nonresponders were not observed to have a change in sleep parameters. CONCLUSIONS These findings suggest that trazodone could be effective therapy for patients with OSA without worsening hypoxemia. Future studies should focus on underlying mechanisms and combination therapies to eliminate OSA. Clinical trial registered with www.clinicaltrials.gov (NCT 01817907).

On the cutting edge of obstructive sleep apnoea: where next?

Obstructive sleep apnoea is a common disease that is now more widely recognised because of the rise in prevalence and the increasingly compelling data that shows major neurocognitive and cardiovascular sequelae. At the same time, the clinical practice of sleep medicine is changing rapidly, with novel diagnostics and treatments that have established a home-based (rather than laboratory-based) management approach. We review the most recent insights and discoveries in obstructive sleep apnoea, with a focus on diagnostics and therapeutics. As will be discussed, management of obstructive sleep apnoea could soon transition from a so-called one size fits all approach to an individualised approach.

Pathogenesis of central and complex sleep apnoea

Central sleep apnoea (CSA) – the temporary absence or diminution of ventilatory effort during sleep – is seen in a variety of forms including periodic breathing in infancy and healthy adults at altitude and Cheyne–Stokes respiration in heart failure. In most circumstances, the cyclic absence of effort is paradoxically a consequence of hypersensitive ventilatory chemoreflex responses to oppose changes in airflow, that is elevated loop gain, leading to overshoot/undershoot ventilatory oscillations. Considerable evidence illustrates overlap between CSA and obstructive sleep apnoea (OSA), including elevated loop gain in patients with OSA and the presence of pharyngeal narrowing during central apnoeas. Indeed, treatment of OSA, whether via continuous positive airway pressure (CPAP), tracheostomy or oral appliances, can reveal CSA, an occurrence referred to as complex sleep apnoea. Factors influencing loop gain include increased chemosensitivity (increased controller gain), reduced damping of blood gas levels (increased plant gain) and increased lung to chemoreceptor circulatory delay. Sleep–wake transitions and pharyngeal dilator muscle responses effectively raise the controller gain and therefore also contribute to total loop gain and overall instability. In some circumstances, for example apnoea of infancy and central congenital hypoventilation syndrome, central apnoeas are the consequence of ventilatory depression and defective ventilatory responses, that is low loop gain. The efficacy of available treatments for CSA can be explained in terms of their effects on loop gain, for example CPAP improves lung volume (plant gain), stimulants reduce the alveolar‐inspired PCO2 difference and supplemental oxygen lowers chemosensitivity. Understanding the magnitude of loop gain and the mechanisms contributing to instability may facilitate personalized interventions for CSA.

Treatment of OSA with CPAP Is Associated with Improvement in PTSD Symptoms among Veterans.

STUDY OBJECTIVES Posttraumatic stress disorder (PTSD) is common among veterans of the military, with sleep disturbance as a hallmark manifestation. A growing body of research has suggested a link between obstructive sleep apnea and PTSD, potentially due to obstructive sleep apnea (OSA) related sleep disruption, or via other mechanisms. We examined the hypothesis that treatment of OSA with positive airway pressure would reduce PTSD symptoms over 6 months. METHODS A prospective study of Veterans with confirmed PTSD and new diagnosis of OSA not yet using PAP therapy were recruited from a Veterans Affairs sleep medicine clinic. All subjects were instructed to use PAP each night. Assessments were performed at 3 and 6 months. The primary outcome was a reduction in PTSD symptoms at 6 months. RESULTS Fifty-nine subjects were enrolled; 32 remained in the study at 6 months. A significant reduction in PTSD symptoms, measured by PCL-S score was observed over the course of the study (60.6 ± 2.7 versus 52.3 ± 3.2 points; p < 0.001). Improvement was also seen in measures of sleepiness, sleep quality, and daytime functioning, as well as depression and quality of life. Percentage of nights in which PAP was used, but not mean hours used per night, was predictive of improvement. CONCLUSIONS Treatment of OSA with PAP therapy is associated with improvement in PTSD symptoms, although the mechanism is unclear. Nonetheless, PAP should be considered an important component of PTSD treatment for those with concurrent OSA. Improving PAP compliance is a challenge in this patient population warranting further investigation. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, ID: NCT02019914. COMMENTARY A commentary on this article appears in this issue on page 5.

An International ISHLT/ATS/ERS Clinical Practice Guideline: Summary for Clinicians. Bronchiolitis Obliterans Syndrome Complicating Lung Transplantation

Pulmonary Medicine, Denver Veterans Affairs Medical Center, Denver, Colorado; Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Denver, Colorado; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Diego School of Medicine, San Diego, California; Section of Allergy, Pulmonary, and Critical Care Medicine, Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; Thoracic Medicine, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia; Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium; Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mt. Auburn Hospital, Harvard Medical School, Boston, Massachusetts

CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea

J Physiol 592.14 (2014) pp 2903–2905 C R O S S TA L K CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea J. E. Orr 1 , B. A. Edwards 2 and A. Malhotra 1,2 Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA, USA Division of Sleep Medicine, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, USA The Journal of Physiology Email: j1orr@ucsd.edu Obstructive sleep apnoea (OSA) is a common disease affecting at least 13% of adult men and 6% of adult women in the United States (Peppard et al. 2013) and is characterized by repetitive collapse (apnoea) or partial collapse (hypopnoea) of the pharyngeal airway during sleep (Sullivan & Issa, 1985; Guilleminault et al. 1986; Young et al. 1993; Hamilton et al. 2004). Recent studies suggest that OSA is a multifactorial condition, and not just an anatomical problem (Wellman et al. 2011; Eckert et al. 2013). Alongside anatomical vulnerability, at least three additional physiological traits interact to contribute to the development of OSA including (1) ineffective upper airway dilator muscles, (2) a low threshold for arousal from sleep, and (3) a hypersensitive ventilatory control system (i.e. high loop gain) (Dempsey et al. 2010). In individual patients, the manifestation of OSA may be the result of one or more combinations of abnormalities, and thus multiple underlying causes may need to be addressed for sleep apnoea to be resolved. Interestingly, recent evidence has questioned whether some of these traits such as a high loop gain are truly pathogenic (i.e. an intrinsic cause of OSA) or merely reflect a consequence of the disorder. Loop gain characterizes the sensitivity of the negative feedback system controlling ventilation and is defined as the size of a ‘corrective’ ventilatory response divided by the size of the ventilatory disturbance that elicits the correction (see Fig. 1); a large response to a small disturbance represents a system with a high loop gain. In favour of an elevated loop gain being an acquired condition (i.e. a consequence of disease) are two investigations whose findings demonstrate that treatment of OSA leads to major reductions in loop gain. Salloum et al. examined the effect of one month of nasal continuous positive airway pressure (CPAP) therapy on the components of the ventilatory control system – plant and controller gain – in a group of recently diagnosed and untreated severe OSA patients (Salloum et al. 2010). They reported that one month of treatment led to reductions in the ventilatory sensitivity to CO 2 (i.e. controller gain), and thus loop gain (as plant gain remained unchanged), back to levels similar to healthy controls. In another study, Loewen et al. measured the dynamic ventilatory response to CO 2 in a group of severe OSA patients before and after one month of CPAP therapy (Loewen et al. 2009). Similar to the study by Salloum et al., Loewen et al. observed that ventilatory sensitivity to CO 2 was markedly diminished following CPAP therapy; taken together, such findings seem to suggest that a high loop gain is a consequence of OSA. However, we would argue that the findings of these two investigations do not provide conclusive evidence that an elevated loop gain is solely a consequence of OSA. An important implication of the aforementioned studies is that one month of effective treatment was sufficient to reverse the consequences of disease and allowed an individual’s ‘intrinsic’ physiology to be assessed. However, studies that have manipulated loop gain in CPAP-treated OSA patients have consistently shown that lowering the ‘intrinsic’ loop gain is associated with an improvement in OSA severity, highlighting the importance of loop gain as a cause of OSA. For instance, administration of oxygen, which is known to lower loop gain via reductions in controller gain, led to marked improvement in OSA among those patients with elevated loop gain at baseline (Wellman et al. 2008; Chowdhuri et al. 2010). No such improvement was observed in patients with low loop gain, highlighting that the intrinsic elevation in loop gain (at baseline) was pathophysiologically important in some OSA patients. In addition to oxygen therapy, the administration of acetazolamide has also been shown to lower loop gain and OSA severity (Edwards et al. 2012, 2013). Furthermore, the use of cardiac resynchronization therapy as a treatment for congestive heart failure additionally improves OSA (Stanchina et al. 2007). In this study, the observed improvement in OSA was strongly correlated with the improvement in circulatory delay, the effect of which is expected to decrease loop gain. Elevated loop gain may be critical to OSA pathogenesis in some patients, and will likely be dependent on the inter- action with other pathophysiological traits that predispose towards apnoea. Depending on the underlying anatomy, loop gain can explain a large proportion of the variance in OSA severity (Wellman et al. 2004; Eckert et al. 2013). Patients with extreme pharyngeal closing pressures (P crit ) were either protected (negative P crit ) or pre- disposed (positive P crit ) to apnoea based on intrinsic anatomy, whereas those with intermediate values were most susceptible to OSA if their loop gain was elevated. Jeremy E. Orr (left) is a Fellow in Pulmonary and Critical Care Medicine at the University of California, San Diego. His current research is focused on the interaction between abnormal ventilatory control and circulatory disorders. Bradley A. Edwards (right) is an Instructor in Medicine in Sleep Medicine at the Brigham and Women’s Hospital and Harvard Medical School. His research focuses on understanding the pathogenesis of the common sleep disorder, obstructive sleep apnoea, as well as developing and assessing novel ways to treat the disorder. Atul Malhotra is a Professor of Medicine in Pulmonary and Critical Care Medicine, as well as the director of Sleep Medicine at the University of California, San Diego. C 2014 The Authors. The Journal of Physiology C 2014 The Physiological Society DOI: 10.1113/jphysiol.2014.271841

Physiology-Based Modeling May Predict Surgical Treatment Outcome for Obstructive Sleep Apnea

STUDY OBJECTIVES To test whether the integration of both anatomical and nonanatomical parameters (ventilatory control, arousal threshold, muscle responsiveness) in a physiology-based model will improve the ability to predict outcomes after upper airway surgery for obstructive sleep apnea (OSA). METHODS In 31 patients who underwent upper airway surgery for OSA, loop gain and arousal threshold were calculated from preoperative polysomnography (PSG). Three models were compared: (1) a multiple regression based on an extensive list of PSG parameters alone; (2) a multivariate regression using PSG parameters plus PSG-derived estimates of loop gain, arousal threshold, and other trait surrogates; (3) a physiological model incorporating selected variables as surrogates of anatomical and nonanatomical traits important for OSA pathogenesis. RESULTS Although preoperative loop gain was positively correlated with postoperative apnea-hypopnea index (AHI) (P = .008) and arousal threshold was negatively correlated (P = .011), in both model 1 and 2, the only significant variable was preoperative AHI, which explained 42% of the variance in postoperative AHI. In contrast, the physiological model (model 3), which included AHIREM (anatomy term), fraction of events that were hypopnea (arousal term), the ratio of AHIREM and AHINREM (muscle responsiveness term), loop gain, and central/mixed apnea index (control of breathing terms), was able to explain 61% of the variance in postoperative AHI. CONCLUSIONS Although loop gain and arousal threshold are associated with residual AHI after surgery, only preoperative AHI was predictive using multivariate regression modeling. Instead, incorporating selected surrogates of physiological traits on the basis of OSA pathophysiology created a model that has more association with actual residual AHI. COMMENTARY A commentary on this article appears in this issue on page 1023. CLINICAL TRIAL REGISTRATION ClinicalTrials.Gov; Title: The Impact of Sleep Apnea Treatment on Physiology Traits in Chinese Patients With Obstructive Sleep Apnea; Identifier: NCT02696629; URL: https://clinicaltrials.gov/show/NCT02696629.

Data-Driven Phenotyping: graphical models for model-based phenotyping of sleep apnea

Sleep apnea is a multifactorial disease with a complex underlying physiology, which includes the chemoreflex feedback loop controlling ventilation. The instability of this feedback loop is one of the key factors contributing to a number of sleep disorders, including Cheyne?Stokes respiration and obstructive sleep apnea (OSA). A major limitation of the conventional characterization of this feedback loop is the need for labor-intensive and technically challenging experiments. In recent years, a number of techniques that bring together concepts from signal processing, control theory, and machine learning have proven effective for estimating the overall loop gain of the respiratory control system (see Figure 1) and its major components, chemoreflex gain and plant gain, from noninvasive time-series measurements of ventilation and blood gases. The purpose of this article is to review the existing model-based techniques for phenotyping of sleep apnea, and some of the emerging methodologies, under a unified modeling framework known as graphical models. The hope is that the graphical model perspective provides insight into the future development of techniques for model-based phenotyping. Ultimately, such approaches have major clinical relevance since strategies to manipulate physiological parameters may improve sleep apnea severity. For example, oxygen therapy or drugs such as acetazolamide may be used to reduce chemoreflex gain, which may improve sleep apnea in selected patients.

Comparative Effectiveness Research in Complex Sleep Apnea

EDITORIAL Comparative Effectiveness Research in Complex Sleep Apnea http://dx.doi.org/10.5665/sleep.3638 Commentary on Morgenthaler et al. The complex sleep apnea resolution study: a prospective randomized controlled trial of continuous positive airway pressure versus adaptive servoventilation therapy. SLEEP 2014;37:927-934. Jeremy Orr, MD 1 ; Shahrokh Javaheri, MD 2 ; Atul Malhotra, MD 1 Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA; 2 Emeritus Professor of Medicine, University of Cincinnati, Cincinnati, OH The area of complex sleep apnea has received considerable attention due to uncertainties in definition, lack of clarity regarding underlying mechanisms, emergence of new tech- nology with potential benefits, and considerable costs associated with various therapeutic approaches. The new data provided by Morgenthaler and colleagues 1 in this issue of SLEEP shed some important light on these issues, although questions remain. We use the term complex sleep apnea to be interchangeable with treatment-emergent central apnea, defined as the devel- opment of central apneas in patients with obstructive sleep apnea after the application of continuous positive airway pres- sure (CPAP). This phenomenon occurs in roughly 5% to 20% of CPAP titrations and has been recognized for some time, although the optimal management of complex sleep apnea has remained unclear. 2,3 Spontaneous resolution of these events over time in the majority of cases with ongoing CPAP therapy suggests that “expectant management” is reasonable. 4,5 On the other hand, the initial experience with CPAP may be a strong determinant of long-term CPAP adherence. As such, patients with considerable residual central apnea on CPAP may benefit from newer devices, if immediate improvement in apnea were to yield improved long-term adherence. Morgenthaler et al. tested the hypothesis that newer devices may be superior to CPAP from the standpoint of residual apnea. 1 The authors randomized 66 OSA patients to receive either adaptive servo-ventilation (ASV) treatment (using ResMed VPAP Adapt SV) or standard CPAP, with a primary outcome of residual apnea hypopnea index (AHI) at 90 days. They found lower residual AHI among ASV treated patients compared to those on CPAP (4.7 ± 8.1 [central 1.1 ± 3.7] vs. 14.1 ± 20.7 [8.8 ± 16.3], P < 0.001). In the overall analyses, 89.7% of ASV treated patients achieved AHI < 10/h, whereas only 64.5% of CPAP treated patients fell below this threshold. The authors found a statistically significant improvement in AHI and there- fore have presented findings supportive of their hypothesis. On the other hand, the data did not reveal a clinically meaningful difference in AHI (10 events per hour as a priori defined by the authors) and thus one could question the clinical relevance of the findings, based on the fact that secondary outcomes including PAP adherence, sleepiness, quality of life, and feeling refreshed were all the same in the ASV group as compared to CPAP. Thus, debate will ensue as to whether the new findings justify the use of new technology as compared to standard CPAP therapy. What are some of the potential reasons for high residual AHI in the CPAP arm of the trial by Morganthaler? Although the authors matched the 2 groups of patients, there were more patients with heart failure (15.2% vs. 3%) in CPAP arm compared to ASV arm. As the authors note, central sleep apnea associated with heart failure may not be suppressed by CPAP in up to 50% of patients, 6 even with long-term use. 7 We also note that in most previous studies of complex sleep apnea, a residual central apnea index of 5 or greater during initial CPAP titration has been used as the threshold, 2,4 whereas the authors of this study used 10 or more. As a result, it is possible that patients were enrolled with increased ventilatory instability that would make them less likely to respond to CPAP. The mechanism of treatment emergent central apnea remains unclear but could include several possibilities: CPAP-induced air leak washing out the anatomical dead space, 8 lowering of upper airway resistance which raises the chemoresponsiveness (i.e., controller gain), and possibly lung stretch reflexes induced by CPAP. 9 Reports of central apnea following oral appliance therapy given to patients with mild to moderate OSA are very rare, suggesting that more than lowering of upper airway resis- tance is at play. However, central apnea following tracheostomy is well described in severe OSA patients, perhaps suggesting that the mechanism underlying baseline OSA may be a critical variable. 10,11 Recent data suggest that patients get OSA for variable reasons, with some having primarily an anatomical problem, whereas others may have dysfunction in pharyngeal dilator muscles and still others may have instability in ventilatory control as a major predisposing factor. 12,13 A concept of personalized medicine is thus emerging, such that therapies targeting underlying mecha- nism may be a method of treating apnea in carefully diagnosed patients. 14 Patients with multiple underlying abnormalities may require combinations of therapies to eliminate apnea. In theory, patients who develop central apneas on CPAP therapy may be those with unstable ventilatory control (elevated loop gain) and those with persistence of central apneas may be those with the highest loop gain values, as previously demonstrated in patients with Cheyne-Stokes breathing. 15,16 Despite the new findings, a number of questions remain regarding the treatment of complex sleep apnea. First, can careful analyses of baseline demographic and polysomno- graphic data predict which patients are likely to benefit from Submitted for publication March, 2014 Accepted for publication March, 2014 Address correspondence to: Jeremy Orr, MD, Division of Pulmonary and Critical Care Medicine, University of California, 9300 Campus Point Drive, MC 7381, La Jolla, CA 92037; E-mail: j1orr@ucsd.edu SLEEP, Vol. 37, No. 5, 2014 Editorial—Orr et al.

Measuring loop gain via home sleep testing in patients with obstructive sleep apnea

Author(s): Orr, Jeremy E; Sands, Scott A; Edwards, Bradley A; Deyoung, Pamela N; Deacon, Naomi; Jen, Rachel; Li, Yanru; Owens, Robert L; Malhotra, Atul