The last decade has seen the introduction of ever-more technologically advanced devices for the noninvasive treatment of sleep-disordered breathing (SDB). Upon the original, straightforward platform of the continuous positive airway pressure (CPAP) flow generator, first introduced in 1981, have been built devices with a dizzying array of capabilities. These include bilevel positive airway pressure (biPAP) flow generators that switch between a lower pressure during expiration [expiratory positive airway pressure (EPAP)] and a higher pressure during inspiration [inspiratory positive airway pressure (IPAP)]; automatically titrating flow generators that detect decreases in airflow and signs of upper airway obstruction in order to vary CPAP or biPAP settings; and devices that target either a set level of ventilation (average volume assured pressure support) or a proportion of the patient's native ventilation or inspiratory flow [adaptive servo-ventilation (ASV)]. The latter devices now combine their original technology with auto-titrating EPAP. There are currently two manufacturers marketing ASV flow generators in the United States (ResMed, San Diego, California markets the S9 VPAP Adapt, and Philips Respironics, Murrysville, Pennsylvania markets the biPAP autoSV Advanced – System One) and a third device is available outside the United States (Weinmann Geräte für Medizin GmbH + Co., Hamburg, Germany produces the SOMNOvent CR) [1▪]. All three devices have shown particular utility in treating patients with central sleep apnea or Hunter–Cheyne–Stokes breathing (CSA/HCSB) as well as combinations of CSA/HCSB and obstructive sleep apnea (OSA), and their use is the subject of this review.
REVIEW OF ADAPTIVE SERVO-VENTILATION TECHNOLOGY
The technology behind ASV is actually quite complicated and beyond the scope of this discussion, but a brief overview (which will be limited to the two devices available in both the United States and overseas) is warranted in order to provide an appreciation of the assumptions and approximations implemented in these devices. This technology, as much as it is available from examination of applicable patents and marketing literature (as precise details are proprietary and not disclosed), has been reviewed in detail elsewhere [1▪,2▪]. In essence, ASV is a negative feedback control system in which a measurement of actual minute ventilation (ResMed) or peak inspiratory airflow (Respironics) is compared with a target value and the difference (error) is used to vary IPAP (and therefore pressure support) on a breath-by-breath basis. The target value for the ResMed flow generator is a percentage (90–95%) of a weighted average of minute ventilation from the preceding 9 min or so with more recent breaths reflected more heavily in the average. The Respironics apparatus takes a similar approach, only targeting the average of peak inspiratory flow and using a moving window of about 4 min. The difficulty inherent in this technology lies in measuring instantaneous airflow without a direct connection to the airway, and despite the presence of the significant amount of airflow that escapes from the mask both on purpose (through ports in or near the mask to wash out exhaled CO2) and by accident (mask or mouth leak). The method by which this is accomplished entails the continuous measurement of delivered airflow and system pressure along with calculations (performed by a microprocessor) that can best be described as deriving an approximation to actual nasal/oral airflow. The ResMed flow generator likely utilizes the series of calculations shown in Fig. 1a[3,4], and the approach used by the Respironics apparatus appears to be one of the two processes in Fig. 1b [5,6]. In both devices, the operator may set a variety of fixed or automatically calculated back-up rates and both now also include the ability to auto-titrate EPAP to maintain airway patency. The latter algorithms are well beyond the scope of this discussion.
HOW DOES ADAPTIVE SERVO-VENTILATION SUPPRESS CENTRAL SLEEP APNEA/HUNTER–CHEYNE–STOKES BREATHING?
The theoretical basis underlying the ability of ASV to suppress CSA/HCSB requires that the time constant, controller gain, and other attributes of the feedback algorithm be chosen so as to ensure that the amount of pressure support supplied by the device is anticyclic to the patient's own ventilation as a reflection of ventilatory drive [1▪]. ASV was developed as a treatment modality for hypocapnic periodic breathing, that is, CSA/HCSB. The pathogenesis of CSA/HCSB is largely explained by the presence of an apneic threshold for PaCO2 that exists only during non rapid eye movement sleep, when the supratentorial contribution to ventilatory drive is lost [7–9], whereas the SDB associated with opioids or neuromuscular ventilatory failure is generally accompanied by varying degrees of hypercapnia and is frequently less amenable to ASV therapy. CSA/HCSB is characterized by central apneas or hypopneas interposed between intervals of hyperventilation; HCSB is differentiated from CSA by a crescendo-decrescendo pattern of tidal volumes during the intervals of hyperventilation. The central hypopneas and apneas increase PaCO2, stimulating chemoreceptors and prompting the ensuing period of hyperventilation. The hyperventilation depresses PaCO2 to a level at or below the apneic threshold, resulting in decrescendo breathing followed by a central hypopnea or apnea (in HCSB) or an abrupt central apnea in CSA. The time that passes before changes in pulmonary venous pCO2 are detected by the central chemoreceptor, and excessive controller gain are factors thought to destabilize ventilatory control, and the periodic breathing of CSA/HCSB is a direct manifestation of cyclic variations in inspiratory drive . A similar phenomenon likely is responsible for CSA/HCSB in patients with cerebrovascular disease . ASV counterbalances this waxing and waning of inspiratory drive by varying the degree of pressure support: decreasing pressure support when inspiratory drive is high and increasing pressure support when inspiratory drive declines. Consequently, the combination of the patient's own inspiratory drive and that of the ASV device sums to maintain a more constant degree of ventilatory drive, thus damping the variations in tidal volume [12,13].
The salutary effects of the acute application of ASV to patients with CSA/HCSB due to congestive heart failure (CHF) can no longer be disputed, as well as the overall superiority in this regard for ASV over CPAP, biPAP-S, biPAP-S/T, or oxygen monotherapy [14,15▪]. In this setting, polysomnography or respiratory polygraphy consistently shows a higher degree of improvement in, and more patients with normalized values of, apnea-hypopnea index (AHI), oxyhemoglobin desaturation index, and parameters related to sleep continuity. The last 18 months have seen increasing publication of short-term and long-term studies examining surrogate endpoints related to CHF morbidity including randomized controlled trials (RCTs). In addition, studies related to technical aspects of ASV have also appeared.
Short-term results of adaptive servo-ventilation treatment for central sleep apnea/hunter–cheyne–stokes breathing in congestive heart failure
Javaheri et al. have called attention to the possibility that injudicious choice of ASV settings, particularly of EPAP with a resulting increase in intrathoracic pressure, might have a deleterious effect on cardiac hemodynamics due to excessive reductions in preload. Conversely, the use of ASV could actually improve hemodynamics due to the reduction in preload in combination with reductions in afterload. Yamada et al.[16▪▪] examined this issue during right heart catheterization in 11 normal controls and 34 patients with chronic, stable CHF. Patients had ejection fraction by echocardiography of greater than 45%, New York Heart Association (NYHA) functional class II or III, and plasma brain natriuretic peptide (BNP) greater than 100 pg/ml. Control patients were suspected to have ischemic heart disease, but no significant coronary artery disease following coronary angiography. None of the patients had SDB. Measurements were made before and after 15 min of ASV treatment using a ResMed Autoset CS flow generator (a predecessor of the S9 VPAP Adapt) using the default settings of EPAP = 5 cm H2O and pressure support range of 3–10 H2O; back-up rate setting is not reported but was probably the default value. Outcome measures were echocardiographic variables, BNP, and hemodynamic variables from the right heart catheterization. Stroke volume index (SVI), the primary outcome measure, declined slightly in the control group exposed to ASV, as might be expected in individuals with normal hearts operating on the Frank–Starling curve. Individual patients experienced either increased SVI (15/34) or decreased SVI (19/34). Heart rate, systolic blood pressure, and pulmonary capillary wedge pressure (PCWP) did not change in either group. After multivariate analysis, significant predictors of improvement in SVI were baseline PCWP and mitral regurgitation area/left atrial area, which revealed a linear relationship. The authors speculated that the latter finding was related to improvement in left ventricular size because of reduced preload; left ventricular dilatation is known to produce functional mitral regurgitation by stretching the papillary muscles, thereby tethering the mitral valve leaflets and preventing full closure. Unfortunately, the authors did not include hemodynamic and echocardiographic assessments that could have supported this mechanism. Nevertheless, other investigators have reported that the application of CPAP or biPAP acutely reduces functional mitral regurgitation (when increasing ejection fraction) during exacerbations of CHF . The results reported by Yamada et al. were limited by the relatively low values of EPAP utilized and the lack of detailed information concerning the level of pressure support being applied (a minimum of 3 cm H2O and a maximum of 10 cm H2O, which translates to settings as high as 15/5 cm H2O or as low as 8/5 cm H2O depending on whether periodic breathing (PB) was or was not present). The authors reported that the patients were awake, but there was no electroencephalographic documentation of sleep/wake status; as patients are usually sedated for cardiac catheterization, some of the patients may have been asleep and exhibiting greater degrees of PB, although PB can occasionally be present in CHF patients even when awake.
Adverse outcomes in CHF have been attributed, in part, to excessive beta-1 adrenergic tone; hence the use of central nervous system-active beta-adrenergic antagonists has become a standard of care . Patients with CHF complicated by CSA/HCSB are known to express additional sympathetic over activity, and therefore reductions in sympathetic tone resulting from ASV treatment of CSA/HCSB could provide further support for using this device in such patients. An early study was reported by Pepperell et al. in patients with chronic symptomatic systolic heart failure (NYHA class II–IV) and SDB that was almost exclusively CSA/HCSB. Using a prospective RCT design comparing Autoset CS (default settings) with sham ASV, these investigators found that urinary metanephrines declined after 4 weeks of ASV treatment while increasing slightly after sham ASV. More recently, Ushijima et al. examined this issue in 57 patients, 70% of whom had CSA/HCSB of varying degrees without OSA, left ventricular ejection fraction (LVEF) less than 45% and NYHA functional class I, II, or III. All patients underwent acclimatization to ASV for 30 min. Patients were randomized between ASV (n = 29; ResMed Autoset CS at default settings for 20/29 and EPAP = 4 cm H2O/maximum pressure support = 8 cm H2O for 9/29) and CPAP (n = 28; using the median airway pressure obtained during the acclimatization). A total of 76 and 71% of the patients in each group, respectively, were receiving chronic beta-blocker therapy. Integrated skeletal muscle sympathetic nerve activity (SNA), a reflection of central nervous system sympathetic outflow, was measured during 10 min without treatment and then during 30 min of either ASV or CPAP application. The degree of muscle SNA declined significantly from baseline in the ASV group but not in the CPAP group. Unfortunately, these investigators did not include polysomnographic (PSG) monitoring as part of the experimental protocol, and therefore it is not known what the effect of either modality might have been on SDB, nor is it definitively known whether the patients were awake or asleep.
It is known that CSA/HCSB is more prevalent in patients with chronic kidney disease (CKD), and many of these patients also suffer from CHF. The severity of SDB seems to correlate with both CKD stage and the severity of CHF, when studied retrospectively . However, whether there is a bidirectional effect (as discussed by Jhamb and Unruh  for OSA in this issue) in which treatment of CSA/HCSB affects CKD outcome remains unknown. A study by Yoshihisa et al.[23▪] recently investigated this issue in 50 patients with stable CHF (NYHA class >II, LVEF <50%, all receiving standard pharmacological therapy including beta blockers) with moderate-to-severe SDB that was predominantly CSA/HCSB. Patients underwent one night of diagnostic PSG followed by a second night of PSG with ASV titration using a ResMed device. During the titration, EPAP was adjusted to suppress OSA and pressure support limits were varied to eliminate CSA/HCSB, although back-up rate was set to the automatic mode. AHI fell from a mean ± SD of 37.3 ± 18.2/h during the baseline night to 9.1 ± 9.1/h on ASV, accompanied by statistically significant improvements in renal function as reflected in both cystatin C and the estimated glomerular filtration rate (eGFR) calculated using cystatin C. As N-terminal proBNP also improved, it may be that the effect on renal function was mediated by improvement in CHF. Nevertheless, the fact that these findings occurred after only a single night of ASV treatment provides much food for thought.
Long-term (≥3 months) follow-up of adaptive servo-ventilation treatment for central sleep apnea/hunter–cheyne–stokes breathing in congestive heart failure
Only recent investigations enrolling patients with predominantly CSA/HCSB will be presented. Two prospective observational studies have examined long-term effects of ASV on cardiac function, and one also included SNA [24,25]. Kourouklis et al. used respiratory polygraphy to screen 85 patients with stable CHF and identified those with moderate-to-severe SDB (AHI ≥15/h). Thirty-eight patients agreed to diagnostic PSG, after which eight patients with OSA and nine with CSA/HCSB agreed to proceed with the study. The nine CSA/HCSB patients underwent a second night of PSG, during which an ASV titration was performed using the ResMed Autoset CS2 (a more recent predecessor of the S9 VPAP Adapt). There is no description of the titration protocol, but the aim of reducing AHI to or less than 5/h was achieved in that mean ± SD of treated AHI was 3.5 ± 0.9/h. Patients were either NYHA class II or III, and almost 90% were on chronic beta-blocker therapy. Echocardiography at baseline and after 6 months of compliant ASV use (>5 h/day) revealed significant improvements in left ventricular end-systolic volume and LVEF. Interestingly, there was also improvement in tricuspid annular plane systolic excursion, a measure of right ventricular function. In terms of performance status, at baseline the CSA/HCSB patients were distributed between NYHA class II (n = 5) and class III (n = 4). After 6 months of ASV use, patients transitioned toward lower NYHA class, including class I (n = 2), class II (n = 6), and class III (n = 2). Similar results were reported by Koyama et al. in a study of 19 patients with CHF with predominantly CSA/HCSB on PSG. They studied 10 patients who were compliant with ASV treatment (6.4 ± 0.6 h/night for 6 months using an Autoset CS with default programming) compared with nine who refused this therapy or exhibited minimal use (0.4 ± 0.5 h/night) and remained on conventional pharmacological management. There were no improvements in echocardiographic metrics of left ventricular function or of plasma BNP levels in the latter group, whereas those who used ASV exhibited improvements in LVEF, left ventricular end-diastolic volume, left ventricular end-systolic volume, and BNP. These investigators also assessed cardiac SNA using 123meta-iodobenzylguanidine myocardial scintigraphy. Both washout ratio and delayed heart-to-mediastinal ratio were used as measures of cardiac SNA. At baseline, washout ratio and heart-to-mediastinal ratio correlated with AHI and central apnea index, indicating that CSA/HCSB was associated with greater cardiac SNA. Both indices improved in the ASV group but not in those patients with no or minimal ASV adherence after 6 months of follow-up.
ASV may have a role in ameliorating renal failure in patients with CSA/HCSB and CHF. Owada et al.[26▪▪] performed an observational study in 80 patients with stable CHF (NYHA class >II), CKD (eGFR <60 ml/min/1.73 m2) and moderate-to-severe, predominantly central, SDB (AHI >15/h). Patients who accepted and were adherent to ASV use (n = 36) were compared with those who refused ASV or discontinued its use (n = 44). After 6 months, the ASV group demonstrated improvements in NYHA class, BNP, creatinine, cystatin C, noradrenaline, and eGFR as well as the echocardiographic measurements of LVEF, left ventricular mass index, left atrial volume index, and E/E’. None of these metrics improved in the non-ASV group. Lastly, a robust improvement in event-free survival was enjoyed by those individuals using ASV at home.
Four recent studies are notable for their use of an RCT study design, one of which included outcome variables that measured prognosis. Yoshihisa et al.[27▪▪] randomized 36 patients with heart failure and preserved ejection fraction (diastolic dysfunction) and moderate-to-severe, predominantly, central SDB to receive treatment with either ASV plus conventional pharmacotherapy or pharmacotherapy alone. Titration of ASV was performed in a manner similar to that described by these investigators in an earlier study, detailed above [23▪]. In addition to obtaining echocardiography, plasma BNP and high-sensitivity troponin T, and eGFR (Modification of Diet in Renal Disease formula), they also analyzed event-free survival, in which events were defined as cardiac death or rehospitalization. After 6 months of follow-up, NYHA class, BNP, and two measures of diastolic function [ratio of early transmitral flow velocity to mitral annular velocity (E/E’) and left atrial volume index] improved in the ASV group, whereas high-sensitivity troponin-T was unchanged. Of particular interest given the negative results of the CanPAP trial,  event-free survival was appreciably higher in the ASV-treated individuals compared with those receiving pharmacotherapy only.
The second RCT was reported by Kasai et al.[29▪▪] and examined neuro-hormonal measures after 3 months of ASV treatment in patients with stable systolic CHF (LVEF <50%; NYHA class ≥II), on optimal pharmacological therapy (74% receiving beta blockers), and with CSA/HCSB that did not suppress with CPAP treatment. Patients with moderate-to-severe CSA/HCSB (AHI ≥15/h, ≥50% of events central in mechanism) were recruited who had been receiving CPAP therapy for at least 3 months but on repeat PSG with CPAP still exhibited an AHI of at least 15/h. Patients were then randomized to either CPAP or the Respironics HeartPAP (similar to the biPAP autoSV Advanced – System One, except employing fixed EPAP) and re-evaluated after 3 months. Patients were manually titrated on their assigned device at the inception of the study: CPAP was adjusted from 4 to 12 cm H2O in order to maximally suppress obstructive apneas, hypopneas, and snoring as well as CSA/HCSB; and ASV by titrating fixed EPAP in the same manner as CPAP (except no higher than 10 cm H2O), setting minimum IPAP to EPAP or EPAP + 2 cm H2O, and maximum IPAP to minimum IPAP + 10 or 12 cm H2O. The automatic back-up rate setting was used initially but, if CSA was not suppressed, this setting was changed to a fixed rate starting at 10 breaths/min and titrating upward as necessary. Patients were assessed by echocardiography, PSG, plasma BNP, arterial blood gases, 24-h urinary norepinephrine excretion, 6 min walk distance (6MWD), and the 36-Item Short Form Survey (SF-36) quality-of-life instrument at baseline and after 3 months of treatment. Twelve patients completed the ASV arm of the study, whereas 11 completed the CPAP arm. Not unexpectedly, AHI was significantly lower in the ASV group compared with the CPAP group at 3 months; moreover, ASV adherence exceeded CPAP adherence by an average of almost 1 h/night. Within-group and between-group comparisons revealed that plasma BNP, LVEF, mitral regurgitation area, and left ventricular end-systolic diameter all improved with ASV and that ASV was superior to CPAP. Within-group comparisons for urinary norepinephrine excretion and 6MWD were not significant, but ASV was superior to CPAP in the between-group analysis. Quality-of-life score by SF-36 also showed superiority of ASV over CPAP. Interestingly, mean PaCO2 at 3 months was higher in the ASV patients compared with that in the CPAP patients.
A third RCT compared ASV treatment plus standard pharmacotherapy with standard pharmacotherapy alone, and incorporated a 3-month follow-up [30▪▪]. Assessments included cardiac function (echocardiography, plasma BNP, serum troponin I) and 6MWD, and the treatment arm utilized the ResMed Autoset CS2 fixed to the default settings. Fifty-one patients with severe CHF (LVEF <40% or NYHA class ≥III) underwent PSG and had HCSB occupying greater than 25% of total sleep time (TST) All were randomized into the study, but only 30 completed the protocol, evenly split between the intervention and control groups. Reasons for dropping out included changes in medications, lack of adherence to ASV (remaining patients averaged 6.4 ± 1.1 h/day of use), and one control patient who expired. All had prominent HCSB, averaging 63 ± 22% of TST in the ASV group and 68 ± 17% of TST in the controls, with AHI values of 27 ± 18/h and 32 ± 13/h, respectively. Compared with the control group, the ASV patients enjoyed significant improvements in LVEF, NYHA class, and 6MWD, whereas plasma BNP and serum troponin I were unchanged. Using death from CHF as the endpoint, survival analysis showed a trend toward improvement in the ASV group compared with controls even in this small group of patients followed for only 3 months (P = 0.071).
The last report to be reviewed is a randomized, parallel design study of systolic heart failure patients with SDB who received either standard therapy (n = 35) or standard therapy along with ASV (n = 37) [31▪▪]. The primary outcome measure was LVEF, whereas secondary outcomes included N-terminal proBNP, eGFR (by MDRD) and quality of life by SF-36, Minnesota Living with Heart Failure Questionnaire, and Fatigue Severity Scale. Over the course of a 3-year period, patients with stable CHF (LVEF ≤ 40%) and SDB (AHI ≥ 20/h) as documented by PSG were recruited and 42 completed the entire protocol. Examining outcomes at baseline and 12 weeks, ASV therapy significantly decreased AHI from a mean of 48/h to 11/h but did not change significantly in the control group. The average titrated value of EPAP in the ASV group was 8.1 ± 1.7 cmH2O and the titrated maximum IPAP averaged 14.0 ± 5.3 cmH2O; automatic backup rate was used in all. There was no between-group difference in the primary outcome, with both therapeutic strategies showing slight LVEF increases at 12 weeks regardless of whether analyzed by intention-to-treat or per-protocol methodology. However, in the ASV group, the reduction of N-terminal proBNP was significantly greater than in the control group. There were no significant differences in SF-36, Minnesota Living with Heart Failure Questionnaire, or Fatigue Severity Scale. The patients in this study had severe SDB and included patients with predominantly OSA as well as predominantly CSA/HCSB. Overall, the central AHI averaged about 20/h of sleep. In a subanalysis that separately examined patients with predominantly OSA versus those with CSA/HCSB (21 patients in each category), the change of LVEF from baseline to 12 weeks was similar regardless of the mechanism for SDB.
As an adjunct to optimal pharmacological management, ASV shows considerable promise as a means to improve outcomes in patients with CHF complicated by CSA/HCSB. Recent studies have demonstrated improvements in cardiac function, plasma BNP, quality of life, and even event-free survival in such patients; these investigations now include several small RCTs. Most studies have incorporated titration of ASV settings during overnight PSG, helping to ensure that suppression of SDB is optimized without adverse hemodynamic consequences. Large RCTs will be necessary to demonstrate the ultimate role of this therapeutic modality in patients with CHF and SDB.
Financial Disclosures: Dr Brown has chaired, co-chaired, and continues as a member of the Polysomnography Practice Advisory Committee of the New Mexico Medical Board and serves on the New Mexico Respiratory Care Advisory Board. He currently receives no grant or commercial funding pertinent to the subject of this article.
Dr Javaheri has received research grants from Philips Respironics and honoraria for lectures from ResMed and Philips Respironics.
Conflicts of interest
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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Study that demonstrated an acute improvement in renal function (cystatin C level and eGFR calculated using cystatin C) when CSA/HCSB was suppressed by ASV in patients with systolic heart failure.
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Prospective observational study demonstrating an improvement in eGFR and event-free survival in patients with CKD, predominantly central SDB, and CHF who received 6 months of treatment with ASV. Patients who refused or were nonadherent to ASV did not experience these benefits.
27▪▪. Yoshihisa A, Suzuki S, Yamaki T, et al. Impact of adaptive servo-ventilation
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RCT comparing CPAP with ASV in patients with systolic heart failure and CSA/HCSB. After 3 months, ASV patients had better adherence to device use, lower plasma BNP, mitral regurgitation area, and left ventricular end-systolic diameter as well as increased LVEF and better quality of life by SF-36
30▪▪. Hetland A, Haugaa KH, Olseng M, et al. Three-month treatment with adaptive servoventilation improves cardiac function and physical activity in patients with chronic heart failure and Cheyne-Stokes respiration: A prospective randomized controlled trial. Cardiology 2013; 126:81–90.
RCT comparing standard pharmacotherapy to pharmacotherapy plus ASV in patients with systolic heart failure and CSA/HCSB. After 3 months of treatment, ASV patients had significant increases in LVEF, improved NYHA class, and longer 6MWD as well as a trend toward reduced CHF mortality.
31▪▪. Arzt M, Schroll S, Series F, et al. Auto-servoventilation in heart failure with sleep apnoea: a randomized controlled trial. Eur Respir J 2013; 42:1244–1254.