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_()0<)m&. .� * .�& .��&�EE�!EEEEE�(�(�!EEE<)EEEE�������������������������������������������������������������������� .EEEEEEEEE: Z:Adaptive servo Ventilation: Friend or Foe?
Ana Pais*, Luiz Menezes Falc�o**
* Department of Internal Medicine of the Santa Maria Hospital/CHLN. Lisbon, Portugal.
**MD, PhD, Cardiologist. Department of Internal Medicine of the Santa Maria Hospital/CHLN. Lisbon. Faculty of Medicine, University of Lisbon, Portugal.

* Corresponding Author:  Luiz Menezes Falc�o.
Address for correspondence: Department of Internal Medicine,
University Hospital Santa Maria, Faculty of Medicine of Lisbon,
Avenue Prof. Egas Moniz, Lisboa 1649-035, Portugal.
 E-mail: luizmfalcao@sapo.pt

The authors report no relationships that could be construed as a conflict of interest.

Keywords: adaptive servo ventilation; central sleep apnea; chronic heart failure; heart failure with preserved ejection fraction (HFpEF); heart failure with reduced ejection fraction (HFrEF) .
 .

Abstract
    Adaptive Servo ventilation (ASV) is a type of non-invasive ventilation device, commonly employed by sleep physicians, using oscillatory positive airway pressure (PAP) to treat central sleep apnea (CSA).      CSA is a common entity in heart failure patients.  
    SERVE HF trial results, demonstrate the hazard effects of this device therapy in HF patients with reduced ejection fraction (HFrEF). Some methodological issues are being raised about the consistency of this study. Ongoing trials could help us, in the future, to definitely define the risks and the benefits of ASV device therapy.

Introduction
    Sleeping disorders are highly prevalent in heart failure patients, occuring in approximately 50% of these patients. Two major subtypes are identified: Obstructive sleep apnea (OSA) and central sleep apnea (CSA).  The majority of patients in sleep clinics are diagnosed with OSA, and only a small number with CSA.  OSA is a well known cause and risk factor for the development of HF, whereas CSA may be seen as a consequence of HF. Those patients with HF and CSA have higher morbidity and mortality than their counterparts without CSA. [1, 2]

Pathophysiology of Sleeping Breathing Disorders (SBD)
    In OSA, repeated episodes of partial or complete upper airway obstruction occur during sleep. This obstruction causes loud snoring, repeated episodes of apnea and hypoxia, and arousals from sleep. CSA by contrast, is caused by the temporary withdrawal of central (brainstem- driven) respiratory drive resulting in cessation of respiratory muscle activity and airflow. In HF, pulmonary congestion during sleep, activates pulmonary stretch receptors that stimulate ventilation, resulting in hyperventilation and lowered blood Pco2, triggering an exaggerated compensatory response, resulting in apnea. This apnea produces a significant increase in CO2, resulting in another exaggerated response- hyperventilation- setting up the cyclical pattern of Cheyne stokes respiration. CSA is considered to reflect the severity of HF. [3] Often the distinction between these 2 subtypes of SBD are not easy, as they might coexist (mixed types) or lead to each other, eg the arousal from an obstructive episode can cause hyperventilation and changes in Pco2 initiating cycles of CSA, or a central episode can cause significant arterial deoxygenation leading to loss of airway tone and airway obstruction.
   Intermittent episodes of hypoxia ( caused both from airway obstruction or central apnea/hypopnea), induce a proinflammatory status, and sustained sympathetic stimulation, increasing the release of cathecolamines, resulting in tachycardia, peripheral vasoconstriction, sodium retention and renin-angiotensin-aldosterone (RAAS), activation, increasing the risk of myocardial ischemia, fibrosis and cardiac remodeling. [4-8]


Risk Factors:
    A number of risk factors have been identified for the development of CSA in HF such as: male sex, higher NYHA functional class, lower ejection fraction, waking hypocapnia (Pco2<38mmHg) and/or higher BNP levels. [1, 2, 9-13]

 Diagnosis of CSA:
    The most frequent complaints of patients with CSA are quite inespecific, and often overlap with those with HF without sleeping breathing disorders (SBD) : fatigue, dyspnea, orthopnea, paroxysmal nocturnal dyspnea and nocturia are typical. Daytime sleepiness, which is quite common in OSA, is often absent in patients with CSA. Sometimes, a sleep partner can help us with the diagnosis, reporting unusual breathing pattern. [9, 13]
    The gold standard test for diagnosing CSA is polysomnography. Characteristic findings are cycles of deep, rapid, crescendo-decrescendo breathing followed by periods of hypopnea and/or apnea with absence of thoracic or abdominal muscle activity.
    A common measure of severity of CSA is the AHI ( apnea-hypopnea index) defined by the number of events ( apneas or hypopneas) per hour.  Apnea is defined as a 90% reduction in tidal volume lasting>10seg while hypopnea is a reduction in tidal volume of 50-90%, lasting>10seg, accompanied by >3% decrease in oxyhaemoglobin saturation. According to one study of ambulatory HF patients, the mortality rise progressively with every 5events/hour increase in AHI. [3, 14]


Treatment  in CSA:
    Treatment of CSA should focus on: control of the underlying disease (HF, brain disorders etc), symptomatic relieve and prevention of the pathological consequences. 
    Current treatment approaches include, as a first step, optimization of medical therapy according to the guidelines for managing of chronic heart failure (CHF).  Nocturnal supplemental oxygen or carbon dioxide administration can be, in some cases, helpful. Respiratory stimulants such as theophylline, acetazolamine, or hypnotics, have also been tried, but are not considered reliably effective and safe. Device therapy for CHF and CSA are increasingly being studied and used. CRT (cardiac resynchronization therapy) is offered to symptomatic HF failure patients with LVEFd"35%, in sinus rhythm with a wide QRS complex (e" 130ms) and left bundle branch block (LBBB), despite optimal medical treatment (Class I of recommendation- 2016 ESC guidelines). In small studies of CRT-treated HF patients with documented CSA, CRT increase cardiac output and consequently, reduce CSA and improve quality of sleep. [15] Commonly used nowadays, are the positive airway pressure devices (PAP). Three types of PAP therapy exist: CPAP (continuous positive airway pressure), BiPAP (Bilevel positive airway pressure), and ASV (adaptive servo-ventilation). They have different mechanisms of action and different indications.
CPAP: delivers the same pre-set pressure continuously, to maintain the airway open, and preventing airway collapse. It is mainly used for OSA, but can also be beneficial in cases of mixed SBD with a significant obstructive component. 
BiPAP: device that provides 2 different pressure settings, one for inspiration (IPAP) and other for expiration (EPAP), with a fixed back up rate. It is mainly used to assist in ventilation in COPD (chronic obstructive pulmonary disease) or CSA.
ASV is the most sophisticated form of PAP therapy. Similarly to BiPAP it has an inspiratory and an expiratory pressure but, by contrast, it has a variable, on demand, back up rate. It detects significant reductions or pauses in breathing and intervenes to maintain the patient ventilation at 90% of what had been normal prior to that sleeping event. It is indicated for patients with CSA after BiPAP has failed to reduce AHI or for patients with mixed sleep apnea without response to CPAP or BiPAP. 
   ASV is considered to be more comfortable to the patients than the other PAP options because it adjusts to the patient breathing pattern, resulting in greater regulation of the amount of airflow delivered and creating a more physiological ventilation.[16,17] Nonetheless, the patient must still wear a mask, which makes compliance to therapy an issue. In addition, current large multinational trials, have shown that this type of therapy is not safe in HFrEF patients, and can even increase morbidity and mortality in those patients.
      Transvenous stimulation of the phrenic nerve, is a novel approach for the treatment of CSA, that is       being studied, and presently subject to a randomized trial to evaluate its safety and efficacy [18,19]. It consists of a neurostimulator device that is implanted transvenously in the right or left pectoral region, and is controlled by an external system programmer, to result in bilateral contraction of the diaphragm. In contrast to PAP therapy, it creates a negative intrathoracic pressure (considered safer in cases of reduced LVEF) and requires no patient intervention to function, thus eliminating patient nonadherence.

Adaptive Servo-ventilation for Central sleep apnea (CSA)
   Two manufacturers currently offer ASV devices: ResMed and PhilipsRespironics.
   The ResMed devices prevents under or over ventilation by dynamically increase or decrease IPS (inspiratory pressure support) as needed. When the patient�s minute ventilation falls below the set target, ResMed�s ASV automatically adjusts the inspiratory pressure support to provide the ventilation needed. As breathing stabilizes, the pressure delivered is rapidly reduced back towards the minimum required.  
   In the Philips Respironics ASV, EPAP is automatically determined to respond to obstructive sleep disordered breathing. During periods of airway stability, the device will automatically minimize pressure, while optimizing airway patency. The Philips Respironics ASV devices are also capable of withdrawing IPS entirely during periods of normal breathing.
   In conclusion, ASV devices in general, have the capacity to provide baseline positive pressure to stabilize and maintain the patency of the airway (similar to CPAP) and are capable of delivering additional breaths when apneas or hypopneas are detected (similar to BiPAP). By contrast to BiPAP, during a hyperventilation phase, these devices do not supply the ventilator support, to prevent further exacerbation of hyperventilation, breaking up the periodic breathing cycle typical of CSA. Therefore, ASV devices are superior to the other PAP therapies at normalizing the AHI in patients with CSA or mixed sleep disorders. The wide use of this latter device, led to large randomized trials, evaluating its efficacy and safety. SERVE-HF was a large randomized, controlled, international, multicenter study, designed to assess the effects of ASV on morbidity and mortality in patients with symptomatic heart failure with reduced LVEF and predominant CSA. The results of this study were first presented at the 2015 ESC congress in London and have been published in the New England Journal of Medicine (NEJM).


SERVE-HF results and limitations of the study
   SERVE-HF trial was designed to compare the effect of standard medical treatment plus ASV versus medical treatment alone, in patients with symptomatic chronic heart failure (NYHA class III or IV, or class II, with at least one hospitalization for HF over the preceding 24months), LVEF <= 45%, and predominant severe CSA (AHI >= 15/h and >50% central events). A total of 1325 patients were included in the study and followed for a mean of 3.5 years. The adherence to ASV therapy was considered satisfactory with an average usage of 3.7hours/night. 

   Although, CSA was effectively controlled in the ASV group confirmed by significant reductions in AHI , from 31.2/h at baseline to 6.7/h at 12 months (p<0.001) [20], there was, surprisingly, a statistically significant increased risk for cardiovascular mortality in patients treated with ASV compared with control group. [20] 


Figure 1-  Cardiovascular mortality in SERVE-HF study, during time.

   Two main explanations have been postulated for these results: the first, is that CSA may be a compensatory mechanism in HFrEF population, with hyperventilation-related, increases in end-expiratory volumes, and decrease work of breathing with periodic rest of the respiratory muscles, and secondly, that the positive airway pressure applied by the ASV device, may further reduce the cardiac output in patients with lower ejection fraction. [20-24] 
   Subgroup analyses were also conducted: the degree of CSR (Cheyne-Stokes respiration) at baseline, showing the more detrimental results in the patients with more severe breathing disorder (>50% CSR), and the left ventricular ejection fraction (LVEF), showing the worst results in patients with LVEF <30%.


Figure 2- Cardiovascular mortality in SERVE-HF study, in subgroups of patients, with different percentage of Cheyne- Stokes respiration per night.


Figure3- Cardiovascular mortality in SERVE-HF study, in subgroups of patients, with different LVEF, among those with reduced ejection fraction.

   Based on these results, the AASM (American Academy of Sleep Medicine) released a statement, on May 2015, recommending doctors, to stop prescribing ASV to treat CSA in patients with LVEF<=45%, and to aware all those patients who are already on these kind of treatment for the possible risks . It is also recommended to, before starting on ASV, ecocardiographically assess ejection fraction, to exclude those who are in the higher risk group.
   SERVE-HF findings are not generalized to: HF patients with LVEF >45%, patients with predominant OSA regardless of LVEF, patients treated with ASV for other reasons than HF (eg in opioid users or after acute ischemic stroke [25-30]) or to other PAP devices different from ASV (eg CPAP)
   Methodological issues within this trial, have recently been raised. 
   The first issue is whether, the settings utilized and/or the specific ASV device used in the trial, could be the cause of the increased cardiovascular mortality. SERVE-HF utilized an old fashioned device, that is no longer in clinical use, a device that was set to deliver fixed and mandatory pressure. The pressure utilized could be too low or too high, resulting in inappropriate treatment of CSA or harmful excessive positive pressure. [31] 
   It shouldn�t be forgotten the changing of the SBD phenotype during time. For example, in a fluid overload state, such as heart failure, the shift of fluids, can cause airway obstruction leading to events, predominantly obstructive in nature. That�s why, a fixed EPAP might at times prove inadequate and ineffective, and the checking up of the device should be frequent. [24, 32, 33] In SERVE-HF study, after the first 12 months, the revision of the settings were done only annually. These long intervals without assessment raise the possibility that the negative results, were partially attributable to SDB, even if the last download showed adequate control of sleep apnea. 
   Other issue raised is whether the use of a full face mask is actually beneficial. In SERVE HF study, a full face mask was used. Some authors speculate that a face mask may enhance CO2 rebreathing, leading to elevated levels of CO2 and renal bicarbonate retention, with incomplete clearance during the day, resulting in sustained metabolic alkalosis. Metabolic alkalosis is known to induce cardiac arrhythmias and other adverse cardiovascular events. [34-42]

The fourth issue, was whether the study have included patients that were, actually, sicker at a baseline, than the patients on previous studies. In SERVE-HF, > 70% of patients were NYHA class III or IV ,with LVEF <30%. Those patients have an initial worse prognosis, and might be more prone to the hemodynamic adverse effects of the increased positive intrathoracic pressure induced by the device.

ASV usage in HF patients with preserved ejection fraction               (HFpEF)
    In randomized study including 36 HFpEF patients with CSA, followed up by a mean of 543 days, the cardiac event rate was compared between patients on optimized medical treatment alone versus optimized medical treatment plus ASV. Over 6 months of treatment, the ASV group had a higher event-free rate (94.4%) compared with those in the no ASV group (61.1%, p<0.05). [43]
    Considering these results, we can expect that, the effect of the ASV device on HFpEF patients are different from the effect of this therapy on HFrEF patients, and that, its use, might be safe. However, larger long term studies are required to definitely answer this question. [43]


Ongoing studies and registries:
     Three major randomized controlled trials concerning this problematic are ongoing at the moment.
     The ADVENT-HF trial, is a Canadian study ongoing in Toronto, with the main goal to investigate the effect of ASV therapy in patients with HFrEF and predominant OSA (differing from SERVE-HF study which was concerning about HFrEF patients with predominant CSA). [44, 45]
      The FACE study is a French prospective, observational trial, that concerns about the use of ASV in different subgroups of HFrEF patients with CSA. The goal is to provide complementary data to SERVE HF trial by characterizing CHF populations that are eligible for ASV. [46]
      The CAT HF study is an American trial, evaluating the cardiovascular outcomes of ASV therapy in patients hospitalized for a sudden worsening of their heart failure symptoms (acute decompensated heart failure). The main different from the other trials is that it provides some insight about the effect of ASV in HFpEF patients with CSA. [46]
      The changing of terminology of HF groups presented in the newer ESC guidelines of May 2016, defining three subgroups of HF patients (HFpEF with ejection fraction(EF) >=50%, HFrEF with EF <40%  and the newer entity in between, with EF 40-49%, called heart failure midrange ejection fraction (HFmrEF) ), can lead to conflicting results in these ongoing trials which are still using the older HF terminology.


Conclusions:
   Until the results of these ongoing studies are available, ASV shouldn�t be prescribed to HF patients with LVEF<=45%, while is still considered safe in patients with LVEF>45%.
     




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[45]-Arzt M, Young T, Finn L, et al. Sleepiness and sleep structure in heart failure patients with and without obstructive sleep apnea.�Arch Int Med.�2006;166:1716�22.
[46]- Tamisier R, Damy T, Davy J-M, et al., Adaptive servoventilation (ASV) decreases unplanned hospitalisations in chronic heart failure (CHF) patients with central sleep apnoea (CSA): the French multicentre, prospective FACE cohort study, European Respiratory Society Congress 2015 [abstract]









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