Fig. 3.1
Various components of an adaptive servo-ventilation (ASV) device with automatic (auto) continuous positive airway pressure (CPAP), auto-inspiratory pressure support (IPS), and auto-backup rate. The algorithm driving these three components makes ASV devices effective in treatment of hybrid sleep-related breathing disorders consisting of obstructive (OSA) and central (CSA) sleep apneas and hypopneas. HCSB Hunter–Cheyne–Stokes breathing. (Modified from [49])
Here, we briefly review two features of ASV devices: First , the importance of the variable inspiratory pressure support as it relates to improving the underlying periodic breathing . ASV devices continuously monitor the patient’s ventilation throughout the sleep period in a moving window of several minutes’ duration. By having information regarding values of the current minute ventilation, ASV devices assist the patient’s breathing if it falls anywhere below 90–95 % of the recent average ventilation . When the patient’s ventilation decreases below this level, e.g., due to an apnea or hypopnea, the device support is engaged, which should maintain ventilation and prevent development of further events. When the patient is hyperventilating, the inspiratory support decreases and could be zero. In this context, the device ventilation is anti-cyclic to the periodicity of the patient’s breathing. It augments ventilation during the hypoventilatory phase of periodic breathing to avoid consequent hypercapnia and hypoxemia (both of which cause chemostimulation of the peripheral arterial and central chemoreceptors resulting in hyperventilation). It also sufficiently reduces inspiratory pressure support during the hyperventilatory phase of periodic breathing to avoid undue hypocapnia (which is chemoinhibitory). Correction or minimization of periodic-breathing-induced cyclic pulmonary blood gas chemistry is fundamental to ASV being effective in the treatment of HCSB in HF.
The second feature of ASV devices to emphasize is the function of the automatic positive end expiratory pressure in eliminating obstructive sleep-disordered breathing (SDB). This feature is important since in HF, OSA may frequently coexist with CSA. This coexistence was first appreciated in early studies [2, 3], which was the reason sleep breathing disorders in HF were classified as predominantly central or obstructive in nature.
Furthermore, in HF, the phenotype of SA is a moving target and may change acutely depending on sleep stage, position, and fluid status/shift, and chronically with changes in weight, medications, and status of HF. For example, with acute decompensation of HF, fluid accumulation and increased right atrial pressure cause upper airway edema and venous congestion, which could result in further upper airway obstruction. This is another reason why ASV devices with automatic end expiratory pressure algorithms are extremely effective in the treatment of a “hybrid” type of SDB present in the stormy natural history of HF.
Use of PAP Devices for Sleep-Disordered Breathing in HF
1.
OSA
In patients with OSA with or without known HF , the treatment of choice is CPAP [3]. Multiple studies in the general population have shown the efficacy of this device in eliminating OSA. The same principle applies to patients with HF and OSA. In a cohort of Medicare beneficiaries with HF and SA, treatment with CPAP resulted in improved survival, decreased number of hospitalizations, and reduced Medicare costs [14]. Similarly, an observational study from Japan [15] also showed that HF patients with OSA who accept and are adherent to treatment with CPAP have improved survival compared to those patients who either refuse or remain nonadherent to CPAP .
Although CPAP is quite effective in eliminating obstructive events, in some individuals with or without HF, CSA may emerge when CPAP is used. This has been referred to as “complex SA.” In the largest study of patients with OSA [19] and without known HF, the prevalence of persistent complex SA was initially 6 % but decreased to 2 % after several weeks of treatment with CPAP. In regard to HF and complex SA, we first saw development of worsening CSA in an occasional HF and OSA patient during CPAP titration [20]. In a recent large study of patients with HFrEF [32], the prevalence of complex SA was estimated at 15 %. It was not clear if these patients would have suffered from persistent complex SA because repeat titration study was not performed after continued use of CPAP. Rather, CPAP therapy was discontinued and ASV was recommended. Of note, in this study [20], complex SA was defined as on AHI ≥ 15 per hour during CPAP titration with obstructive disordered breathing events < 10 % of these. These are not the usual criteria used to define complex SA [19]. In addition, various diagnostic and therapeutic modalities were utilized including polygraphy, full-night polysomnogram, CPAP, and auto-titrating CPAP.
In the aforementioned observational study [20], 27 patients with complex SA underwent ASV titration with a mean follow up of 14 months. The central apnea index (CAI) decreased from 17/h on CPAP to less than 1/h on ASV with an associated increase in minimum saturation from about 82 to 87 %. With ASV, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), and VO2 max significantly improved, whereas the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) decreased significantly.
2.
CSA
Initially, ASV devices were designed to treat the periodic breathing associated with HF as studies have demonstrated that CPAP fails to suppress CSA in a considerable number of patients. For example, in one overnight study, 53 % of subjects with CSA and HFrEF were nonresponders [16], and 43 % of patients failed to respond to CPAP after 3 months in another study [9]. Furthermore, continued use of CPAP in such patients is actually detrimental, resulting in increased mortality [9]. Patients in whom CPAP failed to suppress CSA had poorer survival when compared to those in whom CPAP was effective [9]. Given the risk of excess mortality, we do not recommend [21] continued use of CPAP in any patients whose CSA is CPAP-nonresponsive (i.e., CPAP fails to lower to an AHI below 15/h) on the first night of titration. Why CPAP does not suppress CSA in a large number of HF patients remains to be elucidated. However, it appears that HF patients with severe CSA are characteristically nonresponders. Further, nonresponders have a lower awake arterial partial pressure of carbon dioxide (PCO2) than responders. A reduced awake PCO2 is a reflection of increased wedge pressure, an augmented ventilatory response, and a high loop gain. In this regard, it has been shown that a high loop gain predisposes to periodic breathing [22, 23].
There are multiple ASV studies in HF patients evaluating treatment of CSA [10, 11, 13, 24–44] and CSA coexisting with OSA [45, 46]. Most of these studies are observational with only two randomized clinical trials (RCT), one in HFrEF [25] and the other in HFpEF [13].
We first review studies in HFrEF. Pepperell et al. [25] utilized sham ASV in the control group [25], the only sham-controlled double-blind RCT. In the sham-controlled study, 30 patients with HFrEF were randomized to either therapeutic ASV (n = 15) or subtherapeutic sham ASV (n = 15). ASV decreased AHI from 25 to 5 events per hour, with a concomitant decrease in urinary metnorepinephine. LVEF did not increase significantly, though the study was only 1 month in duration. In a multiple arms study [24], 14 subjects with CSA and HFrEF were randomized to one night each of ASV, CPAP, bilevel, and oxygen therapy. The ASV device significantly decreased AHI more than the other arms.
There are currently two meta-analyses of ASV devices [47, 48] , with only one [47] exclusively in HF. In this study [47], we performed a systematic review of ASV studies for treatment of SDB in adult patients with HF. We identified studies of ≥ 1 week duration that compared ASV to a control condition (i.e., subtherapeutic ASV, continuous or bilevel pressure ventilation, oxygen therapy, or no treatment). Fourteen studies were identified (N = 5538). Comparing ASV to control conditions, the weighted mean difference in AHI, LVEF, and 6-min walk distance favored ASV.
There are multiple observational long-term studies that assess mortality in patients with HFrEF and CSA using ASV. Jilek et al. demonstrated that HF patients with SDB, primarily CSA, had significantly improved survival compared to those who declined or were nonadherent with PAP treatment [11]. PAP included CPAP and/or ASV Owada et al. [12] evaluated 80 HFrEF patients with chronic kidney disease and demonstrated that ASV improved prognosis of HF, cardiorenal function, and event-free survival including decreased hospital readmissions [12]. Takama and Kurabayashi showed improved 1-year prognosis including decreased mortality in HFrEF patients adherent to ASV compared to nonadherent patients [10].
As noted earlier, there are two RCTs of ASV devices. The one in HFrEF was discussed above. The other trial involves a small number of patients with HFpEF. In this study, Yoshihisa et al. [13] randomized 36 patients with LVEF > 50 % and severe SA (AHI = 37/h, CAI = 12/h of sleep) to either an active group with ASV or standard care. There were 18 patients in each arm. The ASV group demonstrated improved cardiac diastolic function, arterial stiffness, and reduced symptoms compared to the non-ASV group. In Kaplan–Meier (KM) analysis, cardiac events (cardiac death and worsening HF) were significantly less in ASV-treated patients. In Cox analysis, only the use of ASV was an independent predictor of improved cardiac events with a heart rate (HR) = 0.58, confidence interval (CI) = 0.18, 0.8, and p = 0.016.
In summary, the new generations of ASV devices are equipped with sophisticated algorithms providing automatic anti-cyclic variable inspiratory pressure support, automatic positive end expiratory pressure, and an automatic backup rate. They possess the potential to effectively treat hybrid sleep-related breathing disorders consisting of both central and obstructive events and to be responsive and adapt to the changing and dynamic phenotype of the sleep-related breathing disorders observed in congestive HF. We expect that systematic long-term studies with ASV devices will prove efficacy in treatment of CSA and CSA coexistent with OSA. We also hypothesize that adherence to ASV devices is superior to that to CPAP. To that regard, in the Canadian multicenter study, at 12 months, the adherence to CPAP was only 3.5 h. If ASV devices are more effective and have improved adherence compared to CPAP, then ASV therapy should translate to improved survival of patients with HF. Currently two RCTs are in progress. For now, we recommend the use of ASV devices for treatment of CSA in patients with HF if CSA is not suppressed by CPAP during the first night of titration (please see Addendum below). In HF patients with OSA who develop complex SA with CPAP titration, we recommend a reevaluation within 4 weeks with CPAP, and if CSA persists, we recommend ASV therapy.
Addendum
SERVE-HF is a multinational, multicenter, randomized parallel trial assessing the effects of ASV [51] (PaceWaveTM, AutoSet CSTM; the old generation ResMed ASV) with medical management compared to a medical management control. The sample consisted of 1325 patients with symptomatic chronic HF, LVEF ≤45%, and predominant CSA. After submission of the current review article, in May 2015, ResMed declared that the SERVE_HF trial demonstrated a 2.5% absolute increased risk of cardiovascular mortality (a secondary endpoint) per year in the ASV group compared to controls. Furthermore, there were no statistically significant differences between the ASV and control arms for any of the following primary endpoints: (1) all-cause death, (2) unplanned hospitalization (or unplanned prolongation of a planned hospitalization) for worsening HF, (3) cardiac transplantation, (4) resuscitation of sudden cardiac arrest, or (5) appropriate life-saving shock for ventricular fibrillation or fast ventricular tachycardia in implantable cardioverter defibrillator patients.
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