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