Current Treatment Options in Neurology (2013) 15:677–691 DOI 10.1007/s11940-013-0260-7

SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR)

Complex Sleep Apnea Harish Rao, MD, MRCPCH1 Robert Joseph Thomas, MD, MMSc2,* Address 1 Boston Children’s Hospital & Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA Email: [email protected] 2 Division of Pulmonary, Critical Care and Sleep, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA

Published online: 18 October 2013 * Springer Science+Business Media New York 2013

Keywords Complex apnea I Complex sleep apnea I NREM-dominant I CO2 reserve I ECG-spectrogram I Acetazolamide I Carbon dioxide I Oxygen I Oral appliance I Adaptive ventilation I Nasal expiratory positive pressure I Phenotype I Central sleep apnea I Obstructive sleep apnea I Periodic breathing I Treatment

Opinion statement Complex sleep apnea currently refers to the emergence and persistence of central apneas and hypopneas following the application of positive airway pressure therapy in patients with obstructive sleep apnea. However, this narrow definition is an “outcome” and does not capture the spectrum of pathological activation of the respiratory chemoreflex in sleep apnea. The International Classification of Sleep Disorders – 3rd edition recognizes the phenomenon of Treatment-Related Central Sleep Apnea, but the phenotype is usually evident prior to onset of therapy. The key polysomnographic characteristics of chemoreflex modulated and mediated sleep apnea are nonrapid eye movement (NREM) dominance of respiratory events, short (G30 seconds) or long (960 seconds) cycle time with a self-similar metronomic timing, and spontaneous improvement during rapid eye movement (REM) sleep. Thus, the majority of chemoreflex effects go unrecognized due to the bias toward obstructive sleep apnea’s current scoring criteria. Any treatment of apparently obstructive sleep apnea, including surgery and oral appliances, can expose chemoreflex-driven instabilities. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable NREM sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient desynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Novel pharmacological approaches may target mediators of carotid body hypoxic sensitization, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is unlikely to be successful, and the power of multi-modality therapy should be harnessed for optimal outcomes.

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Introduction The first description of central apneas following CPAP treatment probably came from Marrone et al who reported the occurrence of central apneas, hypopneas, periodic breathing and prolonged oxygen desaturations in patients who were started on CPAP. These events occurred in NREM and almost exclusively after arousals or wakefulness periods [1]. The next report of central events occurring after application of CPAP came more than a decade later, subsequently reported by many authors [2]. Thomas et al noted the predominance of sleep apnea in unstable NREM sleep (relative to ease of therapy in REM sleep) in a subset of difficult to treat sleep apnea patients. Since publication of the seminal article by Gilmartin et al who applied the term complexity, the existence, definition, and management have been intensely debated and in many ways divided the sleep medicine world [3]. Complex sleep apnea was originally described in most simple terms as NREM dominant obstructive sleep apnea refractory to CPAP in NREM sleep only. Patients

with this pattern of breathing may manifest any combination of periodic breathing, central and mixed apneas, central and obstructive hypopneas, often remaining subthreshold to central sleep apnea or Cheyne-Stokes pattern definitions [3]. Morgenthaler and colleagues subsequently proposed the development of overt central apnea during titration of CPAP as a ‘defining characteristic’ of complex sleep apnea with a threshold of 5 or greater central apneas and hypopneas per hour of sleep making up greater than 50 % of all respiratory events [4]; this was then adopted by Centers for Medicare Services and most insurers in the United States. In time, this largely “insurance” definition has been used by most investigators. Though associated with CPAP treatment in the classic description, this phenomenon has also been observed with non-PAP treatments for obstructive sleep apnea (OSA), including tracheostomy, maxillomandibular advancement surgery, mandibular advancement device, and other forms of surgical relief [5, 6••, 7].

Prevalence and natural history Several studies have estimated the prevalence of complex sleep apnea syndrome (central sleep apnea 95/h on CPAP) to be in the range of 13 %–15 % in the general sleep center patient population [4, 8–11]. Endo et al reported prevalence of complex sleep apnea in 5 % of Japanese patients, which is lower than reported prevalence in USA and Australia [12]. Risk factors include male gender, history of cardiac disease, increasing age, higher baseline apnea-hypopnea index and central apnea index, hypertension, opioid use, coronary artery disease, stroke, and congestive heart failure [8, 11–13]. It is not clear what proportion of complex sleep apnea patients improve over time with continued CPAP treatment. Dernaika et al in a prospective case-control study documented disappearance of central sleep apnea activity with CPAP in 86 % (12/14) of patients over 2–3 months [14]. Seven of their initial 21 patients were intolerant or lost to follow-up, which suggests possible complex apnea in these patients. Similar findings were reported in a study by Kuzniar et al [9]. Cassel et al reported resolution of complex apnea in some patients, but also reported de novo appearance in patients who did not have such characteristics initially [15]. Clearly, the disease process is dynamic.

Polysomnographic recognition Scoring of respiratory events in sleep apnea patients have traditionally been biased to an obstructive phenotype, though the recent update of the 2007 AASM guidelines has criteria for scoring central hypopneas and short sequences of periodic breathing / Cheyne-Stokes respiration [16]. The guidelines state that central hypopneas should not be scored in the presence of flow-limitation, but ob-

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struction is a common feature of central events, [17] even at simulated altitude [18], the latter being a relatively pure model of chemoreflex-driven sleep apnea. Direct visualization of the upper airway shows collapse at the nadir of the cycle to be common even in polysomnographic “central” disease [19]. Expiratory pharyngeal narrowing occurs during central hypocapnic hypopnea [20], directly supporting the concept that the presence of flow-limitation alone cannot be used to distinguish obstructive and central hypopneas [18]. Complex sleep apnea as currently “defined” requires a central apnea-hypopnea index ≥5/ h of sleep with centrally mediated respiratory events constituting ≥50 % of all respiratory events during CPAP titration, in those who do not fulfill criteria for primary central sleep apnea or periodic breathing on the diagnostic polysomnogram. However, publications of complex apnea did not score central hypopneas or periodic breathing. Thus, we believe that descriptions of low (G5 %) persistence of “complex apnea” are incorrect and reflect reliance solely on scoring classic central apneas [21, 22]. In our center, at least 20 % of obstructive sleep apnea not related to congestive heart failure is recognized to be NREM-dominant (unpublished data, 500 consecutive patients in 2012). The guideline for recognition of “Cheyne-Stokes respiration” also require a cycle duration of at least 40 seconds, but we have shown that even shorter cycle times in the range of 20–25 seconds is typical of NREM-dominant sleep apnea [2], reminiscent of high altitude periodic breathing. The most characteristic feature of chemoreflex driving is not the morphology of individual events but NREMdominance and timing / morphology of sequential events (nearly identical) in a consecutive series of events [23] (Fig. 1). A related dimension is the criteria used for estimating success of therapies. For example, if 4 % oxygen desaturation is used to score hypopneas (as seem common in most treatment studies), significant degrees of baseline and residual disease can be missed. Moreover, adaptive ventilators distort the conventional polysomnogram signals and unless the pressure output of

Figure 1. Polysomnographic phenotype of “complex sleep apnea.” Ten-minute compression snapshot of a CPAP titration. This pattern persisted across all lower CPAP pressures and converted to mostly central apneas with higher pressures, and purely central apneas during a brief trial of nonadaptive bilevel positive pressure. Note the waxing and waning flow and effort, and the metronomic character of respiratory events, especially on the right half of the figure. Flow-limitation is often admixed with these patterns, which “disappear” during REM sleep—a most pathognomonic feature.

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SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR) the devices are used to score events, inappropriate success may be declared. When periodic breathing is not adequately controlled, the primary marker on the polysomnogram is pressure cycling associated with arousals.

Mechanisms Many patients with OSA exhibit varying proportions of central and/or mixed apneas. This suggests OSA is not just increased upper airway (UAW) resistance but that respiratory instability also plays a role. Some patients with OSA exhibit evidence of unstable ventilatory control (increased loop gain), that could be lead to UAW narrowing and obstruction [24]. Increasing chemoreceptor stimulation (via increased inhalation of CO2) reduced UAW resistance in sleeping subjects [25]. More evidence is now available to indicate that breathing stability rather than UAW collapsibility distinguishes OSA patients with obstructive and central events from those with pure OSA [26•]. Complex sleep apnea can be understood in terms of four factors that interact and lead to a final common path for the expression of sleep breathing (and disordered breathing): loop gain, arousal threshold, negative pressure reflex sensitivity and genioglossus responsiveness. Of these, airway collapsibility and control stability are readily manipulated [3]. The dominant pathophysiology for abnormal respiratory control sensitivity appears to be dysregulation of CO2 homeostasis. This is particularly so in the case of hypocapnic complex disease. Sleep unmasks a highly sensitive hypocapnia-induced apneic threshold, where apnea is triggered by small transient reductions in arterial PaCO2 below eupnea, and respiration is not restored [27–30]. Hypocapnia is the basis of development of periodic breathing seen in relation to high altitude, idiopathic central sleep apnea syndrome, heart failure and Cheyne-Stokes respiration, and stroke. Loop gain is higher in men and patients with cardiac failure. Men have a steeper hypercapnic ventilatory response slope during wake state, lighter and more easily disrupted sleep, and develop apnea with much smaller changes in CO2 than women, which may explain the higher prevalence of complex sleep apnea among men [31–33]. Hypoxia exposure during sleep sensitizes the carotid bodies, and a gene-environment interaction is likely. Thus, at one extreme is a patient with severe sleep hypoxia and no periodic breathing, while at the other is a patient with an exaggerated hypoxic or hypercapnic ventilatory response in the absence of hypoxia. Complex apnea is likely in the mid-regions of this biological spectrum. Idiopathic central sleep apnea is the best example of isolated hyperactivity of the ventilatory chemoreflex arc [34]. The exact role of positive pressure therapy in the development (or unmasking) of central apneas is unclear. Reducing the CO2 reserve, arousal induction by pressure discomfort, and activation of lung stretch receptors are possible mechanisms [35] but given the stabilizing effects of CO2, the former is the likely mechanism

Advanced phenotyping of chemoreflex influences on sleep respiration The NREM sleep CO2 reserve can be determined inadvertently during bilevel positive pressure titration in the sleep laboratory, when central apneas or

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periodic breathing may emerge though continuous positive pressure, was well tolerated, and efficacious prior to application of bilevel ventilation. An experimentally precise version of this approach uses bilevel ventilation with measurement of end-tidal CO2 – the difference in end-tidal CO2 between stable breathing and the level just before bilevel-induced periodic breathing or central apneas is the CO2 reserve. This reserve is smaller, 2 to 3 mm Hg, in those with heart failure and predominantly central sleep apnea [26•]. Proportional assist ventilation may also be used to estimate the “ease of induction” of central apnea and periodic breathing, and thus quantify the contribution of enhanced respiratory chemoreflexes to sleep apnea severity [36–40]. This technique requires considerable expertise and is not readily applicable to a clinical laboratory environment. Time series analysis of the electrocardiogram (using heart rate variability and heart rate/respiratory coupling) can provide a map of sleep state oscillations, with the spectral dispersion providing phenotyping information regarding chemoreflex influences [23]. The technique, the ECG-spectrogram, maps coupled oscillations of heart rate variability and respiratory R-wave ECG amplitude modulation. The ECG-derived sleep spectrogram can detect low frequency coupled oscillations with two primary patterns: broad band and narrow band. Elevated narrow band coupling, which detects sequences of central apneas and periodic breathing is noted in patients with complex sleep apnea. Those with the ECG-spectrogram biomarker of strong chemoreflex modulation of sleep respiration also have more severe sleep apnea and greater degrees of sleep fragmentation [41]. A wearable device (FDA approved, M1, www.sleepimage.com) is currently available for clinical and research use. Determination of multiple phenotypic traits can be accomplished by assessing the dynamic flow and pressure responses to positive pressure dial down [42]. In a follow-up study [43], 75 men and women with and without OSA aged 20–65 years were studied on three separate nights. The following were determined - anatomical collapsibility (Pcrit), and nonanatomical factors (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability / loop gain). The key findings, varied substantially between participants. In brief, 36 % of OSA patients had minimal genioglossus muscle responsiveness during sleep, 37 % had a low arousal threshold, 36 % had high loop gain; 28 % had multiple nonanatomical features. Nineteen percent had a relatively noncollapsible upper-airway similar to controls, and in these patients, loop gain was almost twice as high as patients with a collapsible airway, despite comparable apnea-hypopnea indices. Review of the data tables of virtually all publications on complex sleep apnea, regardless of exact criteria, and when available in descriptions of sleep apnea phenotyping approaches, show one common theme – NREM sleep dominance of sleep apnea.

Treatment Positive pressure therapies Supporting ventilation during central apneas and stabilizing PCO2 fluctuations has proven successful in treating complex sleep apnea [44]. Adaptive servo-ventilation devices are “smart” bilevel positive airway pressure devices

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SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR) introduced in the last decade for treatment of central and complex sleep apnea syndromes. The ResMed Adapt SV [45–49] provides a baseline degree of ventilatory support. The subject’s ventilation is servo controlled with a high-gain integral controller (0.3 cms H2O/L/sec/sec, clipped to 4 to 10 cm H2O) to equal a moving target ventilation of 90 % of the long-term average ventilation (time constant 3 min). The Philips Respironics BiPAP autoSV Advanced (flow-targeted dynamic bilevel positive pressure ventilator) provides PAP support to sustain upper-airway patency and averages flow patterns over 4 min [50–52]. The Weinmann SOMNOvent CR is available in Europe and combines auto and adaptive pressure [53]. Devices use different algorithms and are all substantially different such that efficacy or not of one device does not predict outcomes with another. Use of adaptive ventilation in congestive heart failure patients improves sleep apnea as well as cardiac function parameters [54]; major prospective studies are underway [55]. Treatment with adaptive ventilation may be better tolerated than CPAP (but not in all patients) and is reasonably effective in suppressing central apneas and improving oxygenation; positive effects on sleep architecture are far less impressive. In a randomized, cross-over design trial comparing BPAP-ST and VPAP-SV, the adaptive device appeared more effective than BPAP-ST in resolving complex sleep apnea [56]. A recent study confirmed this outcome – adaptive ventilation as superior but the degree of residual sleep fragmentation and poor sleep quality suggests that adaptive ventilation therapy is at best partially effective [44].

Hypocapnia minimization Increasing inhaled CO2 has been tried for decades in the treatment of central apnea. The most recent study by Xie et al evaluated 26 patients and demonstrated the power of CO2 modulation in treating sleep apnea syndromes [57••]. They had obstructive sleep apnea by conventional scoring criteria (AHI 42±5 events/hour with 92 % of apnea obstructive), and were treated with O2 supplementation, an isocapnic rebreathing system in which CO2 was added only during hyperpnea to prevent transient hypocapnia, and a continuous rebreathing system. With isocapnic rebreathing, 14/26 reduced their apnea-hypopnea index (AHI) to 31±6 % of control (PG0.01) (responders); 12/26 did not show significant change (non-responders). The responders vs. non-responders had a greater controller gain, a smaller CO2 reserve but no differences in Pcrit. Hypercapnic rebreathing (+4.2±1 mm Hg PETCO2) reduced AHI to 15±4 % of control (PG0.001) in 17/21 subjects with a wide range of CO2 reserve. Hyperoxia (SaO2 ~95 %–98 %) reduced AHI to 36±11 % of control in 7/19 OSA patients tested [57••]. Increasing anatomic dead space with partial rebreathing is one way of increasing CO2 reserve. This is usually done by adding a cylinder or extra tubing of variable volume. In our previous study, we have shown that keeping CO2 above the apnea threshold with the use of Enhanced Expiratory Rebreathing Space (EERS) to be an effective adjunct to PAP therapy [6••]. Control is achieved with a minimal increase in end-tidal CO2 (2–3 mm Hg). PCO2 manipulation can also be done by bleeding CO2 into the circuit by a more precisely controlled flow-independent method. The positive airway pressure gas modulator (PAPGAM) is an

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investigational device that delivers precisely controlled concentrations of oxygen and CO2. In a small case series, six patients with an average respiratory disturbance index of 43 ± 9 / hour (of sleep) on CPAP treatment improved to 4 ±5.3 / hour with addition of 0.5% -1% of CO2 using PAPGAM [58]. When used alone (without positive airway pressure), dynamic CO2 delivery has the promise of efficacy without hypercapnic, and deserves further study in those with relatively pure periodic breathing [59].

Oxygen Nasal O2 has a long history of use to treat central sleep apnea and periodic breathing [60, 61]. Adding O2 to CPAP may result in better control of complex apnea, with a reduction in responsiveness of peripheral chemoreceptors and loop gain [62]. The limitations include the long term cost and difficulty with reimbursement in ‘non hypoxic’ patients. A recent study in a Veteran’s population showed that O2 has beneficial effects, but the polysomnographic changes were delayed by as much as an hour or more [63]. One change to be aware is that of respiratory event cycle length – which can lengthen with the use of O2. Such a change may “reduce” the respiratory event index but not imply a true stabilization of respiration. Use of O2 also negates use of a desaturation link to score hypopneas. It should be noted that hypoxia levels used to initiate O2 therapy in lung disease are not the threshold for evaluating supplemental O2 for complex apnea treatment moving saturations from the mid to the high 90’s can be beneficial. Supplemental O2 can thus usefully be a component of a multi-modal multi-step approach to management of complex sleep apnea.

Sleep stabilization Most patients, including older individuals or those on benzodiazepines/sedative drugs, exhibit periods of sleep that are not scored as N3 by conventional criteria (or any modification thereof) but clearly have ample low amplitude delta frequency waves. Respiration is usually quite stable during this period (functionally, think of it as slow wave sleep), and if recognized, the same precautions as during conventionally scored slow wave sleep apply. It may be easier to recognize stable and unstable NREM sleep from non-electroencephalographic signals, such as respiration, heart rate variability, and respiratory amplitude modulation of the electrocardiogram [64]. The stability of this slow wave-like (frequency but not amplitude) sleep can cause a false sense of security (of treatment efficacy); it is also important not to change pressures if this state is recognized (unless obstructions and flow limitation are quite overt). Flow can look absolutely normal in this state, and then rather abruptly (often within minute) switch to being quite abnormal. Such switches of stable/unstable state are spontaneous, and disease or treatment needs to deal with this dynamic. The magnitude of post apnea/hypopnea ventilatory overshoot following arousals may perpetuate subsequent respiratory events, contributing to disease severity [65••, 66]. A low arousal threshold in some patients contributes to sleep apnea pathogenesis. Use of benzodiazepine or nonbenzodiazepine sedatives can improve central sleep apnea, sleep, and periodic breathing at high altitude, and sleep during positive pressure titration. Triazolam, temazepam, zolpidem, and clonazepam have all been shown to reduce

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SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR) central apnea activity [67–70]. Eszopiclone increased the arousal threshold and lowered the AHI in patients with OSA (non-hypoxic), with the greatest reduction occurring in patients with low arousal thresholds [71]. Trazadone (at 100 mg) increased the respiratory effort arousal threshold in response to hypercapnia and increased tolerance of higher CO2 levels in patients [72].

Opioid dose reduction Opioids use is a risk factor for development of ataxic breathing and central sleep apnea [73–75]. Opiate-induced complex apnea has some unique features – ataxic breathing, mild hypercapnia, and bradypnea. Decreasing the dose of opiates may help reduce central apneas [76]. In most patients stopping opiates entirely is not possible. The pathophysiology involves modulation of hypoxic and hypercapnic ventilatory responses [77], but opiate receptors are seen all over the respiratory control pathways. Opiate-induced ataxic breathing is quite sensitive to CO2 levels – with ready induction of central apnea and worsening of dysrhythmic breathing with continuous or nonadaptive bilevel positive pressure ventilation. Though these patients tend to show mild hypercapnia, with end-tidal CO2 levels in the high 40s to low 50s, using a NV mask and EERS as needed to hold CO2 in the mid-40s can be useful. We have found the use of acetazolamide to be of consistent benefit. Adaptive ventilation is a double-edged sword in these patients – being able to both enable stable breathing and markedly destabilize breathing.

Carbonic anhydrase inhibition Acetazolamide, a diuretic and carbonic anhydrase inhibitor diminishes the response of the peripheral chemoreceptors to hypoxia, decreases loop gain, and reduces the ventilatory response to arousals [65••, 78, 79, 80•]. In animal models, it has been shown to lower the PETCO2 apnea threshold and widen the difference between the eupneic and apneic PETCO2 thresholds [81]. Acetazolamide has been used to treat central apneas and Cheyne-Stokes breathing in patients with and without CHF [82]. While the results may be statistically significant, the degree of residual sleep apnea is unacceptable as sole long-term therapy. Those with short-cycle (30 seconds or less) periodic breathing not responding to EERS are the best candidates, as in this subset, the time constant of the adaptive ventilators seems too long to optimally entrain. Carbonic anhydrase inhibition with acetazolamide or topiramate can be part of a “lab pharmacology protocol”, and can be used with a nonvented mask / EERS. Acetazolamide has been successfully used as CPAP adjuncts at high-altitude [83••, 84]. Zonisamide [85] and topiramate [86] have carbonic anhydrase inhibitory effects, and could, in theory, be used in the place of acetazolamide. It is not known if the neuronal effects would have an impact on respiratory control integration. Two recent studies have demonstrated the benefit of using acetazolamide at high altitude in patients with OSA. Acetazolamide improved oxygenation, breathing disturbances, and sleep quality by stimulating ventilation in patients with OSA not using CPAP [87]. In another study the same group of authors showed that among patients with OSA spending 3 days at moderately elevated altitude, the combination of acetazolamide and auto-CPAP resulted in better nocturnal oxygen saturation and AHI [83••].

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Clonidine One report describes a potential role for clonidine as adjunctive therapy for hypocapnic central sleep apnea syndromes [88]. In a study of 10 healthy subjects (four females) (age 22.3±3.0 years; BMI 25.5±3.4 kg/m2), subjects were randomized to receive placebo or 0.1 mg/45 kg of clonidine on two separate nights. Clonidine was associated with a decreased hypocapnic apneic threshold relative to placebo (37.3±3.3 mm Hg vs. 39.7±3.4 mm Hg, increased CO2 reserve (-3.8± 1.3 mm Hg vs. -2.8±1.2 mm Hg), and decreased the hypocapnic ventilatory responses (1.6±0.6 L/min/mm Hg vs. 2.5±1.3 L/min/mm Hg). Administration of clonidine did not decrease peripheral ventilatory responses. The hypotensive effect will likely reduce enthusiasm for clinical use, but the concept has merit.

Nasal expiratory positive pressure Nasal expiratory positive airway pressure (Provent, Ventus Medical) generates auto PEEP and increased tracheal tug via increased lung volumes [89•], which may relieve obstructive sleep apnea; efficacy is variable and unpredictable [90]; in our center, about 25 % show acceptable benefits when evaluated during polysomnography. We have treated eight patients with complex/central sleep apnea successfully (unpublished data), including one patient with idiopathic central sleep apnea. This effect of Provent can be enhanced by acetazolamide, similar to the use of the drug with CPAP [84]. We speculate that Provent, while providing increased nasal expiratory resistance also gently increases the end tidal CO2, which may stabilize chemoreflex driven breathing instability [90].

Oral appliances In patients who prefer oral appliances as first line treatment for OSA, it is important to be aware that central apneas can also emerge in these settings [91]. At our center we have used these devices in PAP intolerant complex apnea patients with reasonable but unpredictable success. Residual sleep apnea is typical, and requires adjunctive therapy. “Cocktails” that are currently being used by our patients include oral appliance + acetazolamide, or a benzodiazepine, or supplemental oxygen. One specific use of an oral appliance is as adjunctive to positive pressure, to reduce pressure requirements [92, 93].

Winx/Oral (negative) pressure therapy This new approach [94] (www.apnicure.com) uses a mouth piece to apply gentle negative intraoral suction that moves the tongue and soft palate anteriorly, opening and stabilizing the airway. As positive pressure is not applied, perhaps there is less hypocapnia induction. There is no reason why Winx could not be used with, for example, acetazolamide, to provide complementary and synergistic effects on sleep-breathing, or Winx + nasal oxygen, or Winx + Provent, or indeed Winx + dead space. I have tried all these options in the sleep laboratory and they seem to have potential for benefit in individual patients. Short of actual evaluation in the sleep laboratory, efficacy is not predictable for this subset of patients, and is clearly off-label use.

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Body position manipulation A subset of central and complex apnea patients appear to be very position dependent. These patients are “unfixable” while supine and “angels when nonsupine”. Positional effects in central apnea syndromes have been reported in patients with classic Cheyne-Stokes respiration in the setting of heart failure [95, 96]. A second effect of body position is on fluid redistribution from the caudal to cranial parts of the body [97–101]. The effect is rapid, associated with increased neck circumference, and hypocapnia from increased lung water in those with central apnea. Therapeutic manipulation is currently clunky but a wedge pillow or pillows are options.

Directly targeting carotid body function Potassium channels on type I glomus cells are important in mediating the effects of hypoxia, and thus a key component of the chemoreflex arc. A balance between nitric oxide released by efferent nerve activity and generated by neuronal nitric oxide synthase, carbon monoxide via heme oxygenase-II, and hydrogen sulfide by cystathionine γ-lyase is thought to determine the activity of these potassium channels, which is also dependent on calcium for activity [102]. A recent report of inhibiting hydrogen sulfide formation shows a possible way forward, using the irreversible inhibitor of cystathione-lyase, DL-propargylglycine (PAG), in a coronary artery ligation congestive heart failure model in rats [103]. Compared with sham rats, the heart failure rats exhibited increased breath interval variability and number of apneas, enhanced carotid body afferent discharge and ventilatory responses to hypoxia, decreased heart rate variability, and increased low-frequency systolic blood pressure variability. PAG treatment reduced the apnea index by 90 %, reduced breath interval variability by 40 %–60 %, reversed the enhanced hypoxic carotid body afferent and chemoreflex responses observed in heart failure rats, and reversed autonomic abnormalities. These results show the strength of translational biology and if proven successful can impact the management of enhanced carotid chemoreflexes in sleep apnea in general and in those with central sleep apnea, period breathing, or complex sleep apnea by any definition.

Future directions Improvement in translation of the enormous amount of information on the respiratory chemoreflexes to routine clinical practice requires a reappraisal of our approach to sleep apnea. Current scoring does not adequately capture chemoreflex influences on sleep respiration. Chemorflex influences are encoded in all polysomnographic signals, from oximetry to heart rate variability to respiration. Apart from better scoring techniques to identify central hypopneas and periodic breathing, esophageal manometry, and pulse transit time may be useful to differentiate central and obstructive events, particularly in patients who do not respond well to conventional positive pressure therapy [41]. Measurement of CO2 reserve, loop gain, and mapping coupled sleep oscillations to complement manual / visual phenotyping may be of assistance. Even application of the AASM standards for periodic breathing scoring will be a start. Residual sleep apnea on CPAP is common in complex

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apnea patients, and current CPAP devices allow viewing respiratory waveforms. Machine detected apnea-hypopnea index can be inaccurate, and viewing waveforms should be the clinical standard of efficacy. A high residual index or persistently abnormal waveforms in the absence of major leak is likely complex apnea. Insurance targets for compliance are inadequate and life-long tracking is essential. Single-mode approaches are not likely to be sufficient in complex apnea. Logical combinations of anti-obstructive treatment, sleep state stabilization, and loop gain reduction should be utilized. New drugs that can modulate the respiratory chemoreflex are eagerly awaited.

Compliance with Ethics Guidelines Conflicts of Interest Robert Joseph Thomas has served as a consultant for DeVilbiss HealthCare and GLG Consulting; has received grant support from the NHLBI; holds patents with MyCardio, LLC and PAPGAM; and has received royalties from MyCardio, LLC. Harish Rao declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with animal subjects performed by any of the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

2.

3.

4.

5.

Marrone O, Stallone A, Salvaggio A, Milone F, Bellia V, Bonsignore G. Occurrence of breathing disorders during CPAP administration in obstructive sleep apnoea syndrome. Eur Respir J. 1991;4:660–6. Thomas RJ, Terzano MG, Parrino L, Weiss JW. Obstructive sleep-disordered breathing with a dominant cyclic alternating pattern—a recognizable polysomnographic variant with practical clinical implications. Sleep. 2004;27:229–34. Gilmartin GS, Daly RW, Thomas RJ. Recognition and management of complex sleep-disordered breathing. Curr Opin Pulm Med. 2005;11:485–93. Morgenthaler TI, Kagramanov V, Hanak V, Decker PA. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep. 2006;29:1203–9. Goldstein C, Kuzniar TJ. The emergence of central sleep apnea after surgical relief of nasal obstruction in obstructive sleep apnea. J Clin Sleep Med. 2012;8:321–2.

6.••

Gilmartin G, McGeehan B, Vigneault K, Daly RW, Manento M, Weiss JW, et al. Treatment of positive airway pressure treatment-associated respiratory instability with enhanced expiratory rebreathing space (EERS). J Clin Sleep Med. 2010;6:529–38. A description of adapting the dead space concept to positive airway pressure therapy. 7. Kuzniar TJ, Kovacevic-Ristanovic R, Freedom T. Complex sleep apnea unmasked by the use of a mandibular advancement device. Sleep Breath. 2011;15:249–52. 8. Lehman S, Antic NA, Thompson C, Catcheside PG, Mercer J, McEvoy RD. Central sleep apnea on commencement of continuous positive airway pressure in patients with a primary diagnosis of obstructive sleep apnea-hypopnea. J Clin Sleep Med. 2007;3:462–6. 9. Kuzniar TJ, Pusalavidyasagar S, Gay PC, Morgenthaler T. Natural course of complex sleep

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10.

11. 12.

13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR) apnea—a retrospective study. Sleep Breath. 2008;12:135–9. Kuzniar TJ, Morgenthaler TI. Treatment of complex sleep apnea syndrome. Curr Treat Options Neurol. 2008;10:336–41. Gay PC. Complex sleep apnea: it really is a disease. J Clin Sleep Med. 2008;4:403–5. Endo Y, Suzuki M, Inoue Y, Sato M, Namba K, Hasegawa M, et al. Prevalence of complex sleep apnea among Japanese patients with sleep apnea syndrome. Tohoku J Exp Med. 2008;215:349–54. Kuzniar TJ, Morgenthaler TI. Treatment of complex sleep apnea syndrome. Chest. 2012;142:1049–57. Dernaika T, Tawk M, Nazir S, Younis W, Kinasewitz GT. The significance and outcome of continuous positive airway pressure-related central sleep apnea during splitnight sleep studies. Chest. 2007;132:81–7. Cassel W, Canisius S, Becker HF, Leistner S, Ploch T, Jerrentrup A, et al. A prospective polysomnographic study on the evolution of complex sleep apnoea. Eur Respir J. 2011;38:329–37. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. J Clin Sleep Med. 2012;8:597–619. Jobin V, Rigau J, Beauregard J, Farre R, Monserrat J, Bradley TD, et al. Evaluation of upper airway patency during Cheyne-Stokes breathing in heart failure patients [published online ahead of print May 17, 2012]. Eur Respir J. 2012;40:1523–30. Thomas RJ, Tamisier R, Boucher J, Kotlar Y, Vigneault K, Weiss JW, et al. Nocturnal hypoxia exposure with simulated altitude for 14 days does not significantly alter working memory or vigilance in humans. Sleep. 2007;30:1195–203. Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central sleep apnea. J Appl Physiol. 1995;78:1806–15. Sankri-Tarbichi AG, Rowley JA, Badr MS. Expiratory pharyngeal narrowing during central hypocapnic hypopnea. Am J Respir Crit Care Med. 2009;179:313–9. Westhoff M, Arzt M, Litterst P. Prevalence and treatment of central sleep apnoea emerging after initiation of continuous positive airway pressure in patients with obstructive sleep apnoea without evidence of heart failure. Sleep Breath. 2012;16:71–8. Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med. 2009;5:205–11. Thomas RJ, Mietus JE, Peng CK, Gilmartin G, Daly RW, Goldberger AL, et al. Differentiating obstructive from central and complex sleep apnea using an automated electrocardiogram-based method. Sleep. 2007;30:1756–69.

24.

Jordan AS, Wellman A, Edwards JK, Schory K, Dover L, MacDonald M, et al. Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea. J Appl Physiol. 2005;99:2020–7. 25. Badr MS, Skatrud JB, Simon PM, Dempsey JA. Effect of hypercapnia on total pulmonary resistance during wakefulness and during NREM sleep. Am Rev Respir Dis. 1991;144:406–14. 26.• Xie A, Bedekar A, Skatrud JB, Teodorescu M, Gong Y, Dempsey JA. The heterogeneity of obstructive sleep apnea (predominant obstructive vs pure obstructive apnea). Sleep. 2011;34:745–50. The primary physiological difference between virtually pure REM-dominant obstructive sleep apnea and more "mixed" apnea is a reduced CO2 reserve, not differences in airway collapsibility. 27. Dempsey JA, Smith CA, Blain GM, Xie A, Gong Y, Teodorescu M. Role of central/peripheral chemoreceptors and their interdependence in the pathophysiology of sleep apnea. Adv Exp Med Biol. 2012;758:343–9. 28. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90:47–112. 29. Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3:141–63. 30. Miller YE, Karoor V, Dempsey EC, Fagan KA. Sleepdisordered breathing, hypoxemia, and cancer mortality. Am J Respir Crit Care Med. 2013;187:330–1. 31. White DP, Douglas NJ, Pickett CK, Weil JV, Zwillich CW. Sexual influence on the control of breathing. J Appl Physiol. 1983;54:874–9. 32. Jordan AS, Eckert DJ, Catcheside PG, McEvoy RD. Ventilatory response to brief arousal from nonrapid eye movement sleep is greater in men than in women. Am J Respir Crit Care Med. 2003;168:1512– 9. 33. Hume KI, Van F, Watson A. A field study of age and gender differences in habitual adult sleep. J Sleep Res. 1998;7:85–94. 34. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med. 1995;152:1950–5. 35. Malhotra A, Bertisch S, Wellman A. Complex sleep apnea: it isn't really a disease. J Clin Sleep Med. 2008;4:406–8. 36. Loewen A, Ostrowski M, Laprairie J, Atkar R, Gnitecki J, Hanly P, et al. Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep. 2009;32:1355–65. 37. Meza S, Mendez M, Ostrowski M, Younes M. Susceptibility to periodic breathing with assisted ventilation during sleep in normal subjects. J Appl Physiol. 1998;85:1929–40.

Complex Sleep Apnea 38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol. 2008;105:1389–405. Younes M, Ostrowski M, Atkar R, Laprairie J, Siemens A, Hanly P. Mechanisms of breathing instability in patients with obstructive sleep apnea. J Appl Physiol. 2007;103:1929–41. Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2001;163:1181–90. Thomas RJ. Strong chemoreflex modulation of sleepbreathing: some answers but even more questions. J Clin Sleep Med. 2009;5:212–4. Wellman A, Edwards BA, Sands SA, Owens RL, Nemati S, Butler J, et al. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol. 2013;114:911–22. Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea: identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013. doi:10.1164/ rccm.201303-0448OC. Dellweg D, Kerl J, Hoehn E, Wenzel M, Koehler D. Randomized controlled trial of noninvasive positive pressure ventilation (NPPV) versus servoventilation in patients with CPAP-induced central sleep. Apnea (Complex Sleep Apnea). Sleep. 2013;36:1163–71. Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med. 2001;164:614–9. Koyama T, Watanabe H, Tamura Y, Oguma Y, Kosaka T, Ito H. Adaptive servo-ventilation therapy improves cardiac sympathetic nerve activity in patients with heart failure. Eur J Heart Fail. 2013;15:902–9 [published online ahead of print March 15, 2013]. Koyama T, Watanabe H, Igarashi G, Terada S, Makabe S, Ito H. Short-term prognosis of adaptive servo-ventilation therapy in patients with heart failure. Circ J. 2011;75:710–2. Iwaya S, Yoshihisa A, Nodera M, Owada T, Yamada S, Sato T, et al. Suppressive effects of adaptive servoventilation on ventricular premature complexes with attenuation of sympathetic nervous activity in heart failure patients with sleep-disordered breathing. Heart Vessels. 2013. doi:10.1007/s00380-013-03942. D'Elia E, Vanoli E, La Rovere MT, Fanfulla F, Maggioni A, Casali V, et al. Adaptive servo ventilation reduces central sleep apnea in chronic heart failure patients: beneficial effects on autonomic modulation of heart rate. J Cardiovasc Med. 2013;14:296–300. Randerath WJ, Nothofer G, Priegnitz C, Anduleit N, Treml M, Kehl V, et al. Long-term autoservoventilation or constant positive pressure in

Rao and Thomas

689

heart failure and coexisting central with obstructive sleep apnea. Chest. 2012;142:440–7. 51. Javaheri S, Goetting MG, Khayat R, Wylie PE, Goodwin JL, Parthasarathy S. The performance of two automatic servo-ventilation devices in the treatment of central sleep apnea. Sleep. 2011; 34:1693–8. 52. Arzt M, Schroll S, Series F, Lewis K, Benjamin A, Escourrou P, et al. Auto-servo ventilation in heart failure with sleep apnea - a randomized controlled trial. Eur Respir J. 2012. doi:10.1183/09031936.00083312. 53. Oldenburg O, Bitter T, Wellmann B, Fischbach T, Efken C, Schmidt A, et al. Trilevel adaptive servoventilation for the treatment of central and mixed sleep apnea in chronic heart failure patients. Sleep Med. 2013;14:422–7. 54. Bitter T, Westerheide N, Hossain MS, Lehmann R, Prinz C, Kleemeyer A, et al. Complex sleep apnoea in congestive heart failure. Thorax. 2011;66:402– 7. 55. Cowie MR, Woehrle H, Wegscheider K, Angermann C, d’Ortho MP, Erdmann E, et al. Rationale and design of the SERVE-HF study: treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive servo-ventilation in patients with chronic heart failure. Eur J Heart Fail. 2013;15:937–43. 56. Morgenthaler TI, Gay PC, Gordon N, Brown LK. Adaptive servoventilation versus noninvasive positive pressure ventilation for central, mixed, and complex sleep apnea syndromes. Sleep. 2007;30:468–75. 57.•• Xie A, Teodorescu M, Pegelow DF, Teodorescu MC, Gong Y, Fedie JE, et al. Effects of stabilizing or increasing respiratory motor outputs on obstructive sleep apnea. J Appl Physiol. 2013;115:22–33. The best recent demonstration of phenotypic spectrum of responsiveness to CO2 in sleep apnea patients. Safe use of CO2 will, however, need to make low concentrations effective, such as with concomitant use of positive pressure therapy or even an oral appliance. 58. Thomas RJ, Daly RW, Weiss JW. Low-concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing. Sleep. 2005;28:69–77. 59. Mebrate Y, Willson K, Manisty CH, Baruah R, Mayet J, Hughes AD, Parker KH, Francis DP. Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes. J Appl Physiol. 2009;107:696–706. 60. Sakakibara M, Sakata Y, Usui K, Hayama Y, Kanda S, Wada N, et al. Effectiveness of short-term treatment with nocturnal oxygen therapy for central sleep apnea in patients with congestive heart failure. J Cardiol. 2005;46:53–61.

690 61.

SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR)

Gold AR, Bleecker ER, Smith PL. A shift from central and mixed sleep apnea to obstructive sleep apnea resulting from low-flow oxygen. Am Rev Respir Dis. 1985;132:220–3. 62. Allam JS, Olson EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes. Chest. 2007;132:1839–46. 63. Chowdhuri S, Ghabsha A, Sinha P, Kadri M, Narula S, Badr MS. Treatment of central sleep apnea in U.S. veterans. J Clin Sleep Med. 2012;8:555–63. 64. Thomas RJ, Mietus JE, Peng CK, Goldberger AL. An electrocardiogram-based technique to assess cardiopulmonary coupling during sleep. Sleep. 2005;28:1151–61. 65.•• Edwards BA, Connolly JG, Campana LM, Sands SA, Trinder JA, White DP, et al. Acetazolamide attenuates the ventilatory response to arousal in patients with obstructive sleep apnea. Sleep. 2013;36:281–5. This report demonstrates that acetazolamide has potentially beneficial effects beyond reduction of loop gain in sleep apnea patients. 66. Jordan AS, Eckert DJ, Wellman A, Trinder JA, Malhotra A, White DP. Termination of respiratory events with and without cortical arousal in obstructive sleep apnea. Am J Respir Crit Care Med. 2011;184:1183–91. 67. Quadri S, Drake C, Hudgel DW. Improvement of idiopathic central sleep apnea with zolpidem. J Clin Sleep Med. 2009;5:122–9. 68. Bonnet MH, Dexter JR, Arand DL. The effect of triazolam on arousal and respiration in central sleep apnea patients. Sleep. 1990;13:31–41. 69. Guilleminault C, Crowe C, Quera-Salva MA, Miles L, Partinen M. Periodic leg movement, sleep fragmentation and central sleep apnoea in two cases: reduction with Clonazepam. Eur Respir J. 1988;1:762–5. 70. Nickol AH, Leverment J, Richards P, Seal P, Harris GA, Cleland J, et al. Temazepam at high altitude reduces periodic breathing without impairing next-day performance: a randomized cross-over double-blind study. J Sleep Res. 2006;15:445–54. 71. Eckert DJ, Owens RL, Kehlmann GB, Wellman A, Rahangdale S, Yim-Yeh S, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci. 2011;120:505–14. 72. Eckert DJ, Kehlmann G, Wellman A, White D, Malhotra A. Effects of trazodone on the respiratory arousal threshold and upper airway dilator muscle responsiveness during sleep in obstructive sleep apnea. Sleep. 2011;34:A156–7. 73. Wang D, Teichtahl H, Drummer O, Goodman C, Cherry G, Cunnington D, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. 2005;128:1348–56.

74.

Sharkey KM, Kurth ME, Anderson BJ, Corso RP, Millman RP, Stein MD. Obstructive sleep apnea is more common than central sleep apnea in methadone maintenance patients with subjective sleep complaints. Drug Alcohol Depend. 2010;108:77–83. 75. Charpentier A, Bisac S, Poirot I, Vignau J, Cottencin O. Sleep quality and apnea in stable methadone maintenance treatment. Subst Use Misuse. 2010;45:1431–4. 76. Walker JM, Farney RJ, Rhondeau SM, Boyle KM, Valentine K, Cloward TV, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med. 2007;3:455–61. 77. Teichtahl H, Wang D, Cunnington D, Quinnell T, Tran H, Kronborg I, et al. Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients. Chest. 2005;128:1339–47. 78. Shore ET, Millman RP. Central sleep apnea and acetazolamide therapy. Arch Intern Med. 1983;143:1278–80. 79. Inoue Y, Takata K, Sakamoto I, Hazama H, Kawahara R. Clinical efficacy and indication of acetazolamide treatment on sleep apnea syndrome. Psychiatry Clin Neurosci. 1999;53:321–2. 80.• Edwards BA, Sands SA, Eckert DJ, White DP, Butler JP, Owens RL, et al. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. J Physiol. 2012;590:1199–211. Support for use of acetazolamide in appropriate phentyped sleep apnea patients. The challenge in accurate clinical phenotyping. 81. Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep. Am J Respir Crit Care Med. 2002;165:1251–60. 82. Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Am J Respir Crit Care Med. 2006;173:234–7. 83.•• Latshang TD, Nussbaumer-Ochsner Y, Henn RM, Ulrich S, Lo Cascio CM, Ledergerber B, et al. Effect of acetazolamide and autoCPAP therapy on breathing disturbances among patients with obstructive sleep apnea syndrome who travel to altitude: a randomized controlled trial. JAMA. 2012;308:2390–8. A clear demonstration of the role of "multimodality" therapy targeting combined pathophysiologies. The paper makes a case for the routine use of acetazolamide when sleep apnea patients are exposed to high altitiude. 84. Glidewell RN, Orr WC, Imes N. Acetazolamide as an adjunct to CPAP treatment: a case of complex sleep apnea in a patient on long-acting opioid therapy. J Clin Sleep Med. 2009;5:63–4. 85. De Simone G, Di Fiore A, Menchise V, Pedone C, Antel J, Casini A, et al. Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cy-

Complex Sleep Apnea tosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorg Med Chem Lett. 2005;15:2315–20. 86. Westwood AJ, Vendrame M, Montouris G, Auerbach SH. Pearls & oysters: treatment of central sleep apnea with topiramate. Neurology. 2012;78:e97–9. 87. Nussbaumer-Ochsner Y, Latshang TD, Ulrich S, Kohler M, Thurnheer R, Bloch KE. Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. Chest. 2012;141:131–8. 88. Sankri-Tarbichi AG, Grullon K, Badr MS. Effects of clonidine on breathing during sleep and susceptibility to central apnoea. Respir Physiol Neurobiol. 2013;185:356–61. 89.• Braga CW, Chen Q, Burschtin OE, Rapoport DM, Ayappa I. Changes in lung volume and upper airway using MRI during application of nasal expiratory positive airway pressure in patients with sleep-disordered breathing. J Appl Physiol. 2011;111:1400–9. Potential mechanisms are demonstrated for efficacy of nasal expiratory pressure using imaging techniques. 90. Patel AV, Hwang D, Masdeu MJ, Chen GM, Rapoport DM, Ayappa I. Predictors of response to a nasal expiratory resistor device and its potential mechanisms of action for treatment of obstructive sleep apnea. J Clin Sleep Med. 2011;7:13–22. 91. Avidan AY. The development of central sleep apnea with an oral appliance. Sleep Med. 2006;7:85–6. 92. Denbar MA. A case study involving the combination treatment of an oral appliance and auto-titrating CPAP unit. Sleep Breath. 2002;6:125–8. 93. El-Solh AA, Moitheennazima B, Akinnusi ME, Churder PM, Lafornara AM. Combined oral appliance and positive airway pressure therapy for obstructive sleep apnea: a pilot study. Sleep Breath. 2011;15:203–8. 94. Colrain IM, Black J, Siegel LC, Bogan RK, Becker PM, Farid-Moayer M, Goldberg R, Lankford DA, Goldberg

95.

96.

97.

98.

99.

100.

101.

102.

103.

Rao and Thomas

691

AN, Malhotra A. A multicenter evaluation of oral pressure therapy for the treatment of obstructive sleep apnea. Sleep Med. 2013;14:830–7. Szollosi I, Roebuck T, Thompson B, Naughton MT. Lateral sleeping position reduces severity of central sleep apnea / Cheyne-Stokes respiration. Sleep. 2006;29:1045–51. Joho S, Oda Y, Hirai T, Inoue H. Impact of sleeping position on central sleep apnea/Cheyne-Stokes respiration in patients with heart failure. Sleep Med. 2010;11:143–8. White LH, Bradley TD. Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea. J Physiol. 2013;591:1179–93. Redolfi S, Yumino D, Ruttanaumpawan P, Yau B, Su MC, Lam J, et al. Relationship between overnight rostral fluid shift and obstructive sleep apnea in nonobese men. Am J Respir Crit Care Med. 2009;179:241–6. Kasai T, Motwani SS, Yumino D, Mak S, Newton GE, Bradley TD. Differing relationship of nocturnal fluid shifts to sleep apnea in men and women with heart failure. Circ Heart Fail. 2012;5:467–74. Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension. Hypertension. 2010;56:1077–82. Elias RM, Bradley TD, Kasai T, Motwani SS, Chan CT. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant. 2012;27:1569–73. Prabhakar NR. Carbon monoxide (CO) and hydrogen sulfide (H(2)S) in hypoxic sensing by the carotid body. Respir Physiol Neurobiol. 2012;184:165–9. Del Rio R, Marcus NJ, Schultz HD. Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure. J Appl Physiol. 2013;114: 1141–50.