Effect of Servo-Ventilation on CO2 Regulation and Heart Rate Variability
Effect of Servo-Ventilation on CO2 Regulation and Heart Rate Variability
Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a condition where the upper airway
 partially collapses and closes. This can lead to sleep problems including low oxygen levels,
 poor sleep, elevated carbon dioxide levels in the blood, and activation of the sympathetic
 nervous system. Results from having disrupted sleep may be excessive daytime sleepiness along
 with behavioral, functional, cardiovascular and cognitive dysfunction. Continuous Positive
 Airway Pressure (CPAP) is the most effective treatment for OSAHS. CPAP stabilizes the airway
 and prevents instability and collapse. Other forms of positive airway pressure that are
 approved for the treatment of OSAHS include automatically adjusting CPAP, Bi-level Positive
 Airway Pressure (BiPAP), and automatically adjusting BiPAP. Automatically adjusting CPAP
 (Auto CPAP) evaluates the airflow pattern and adjusts pressure to optimize airflow. AutoSV
 (Auto Servo Ventilation) is a mode of positive airway pressure used to treat obstructive and
 complex central sleep apnea.

 In the prior study, the investigators found that the Auto S7 device led to more positive
 ventilation outcomes. Specifically, there was prolongation of QTc interval (the calculated
 time from the Q wave to the end of the T wave) and a tendency for greater premature
 ventricular contractions. The mechanistic basis for this could be attributable to excessive
 ventilation and related pro-arrhythmic effects of hypocapnia, though the investigators had
 not performed measures (partial pressure of CO2 (PaCO2) to detect this.

 In the current study, the investigators would like to investigate the hypothesis that the S7
 device leads to lower PaCO2 levels than other devices, and whether these effects are
 augmented in individuals with complex sleep apnea in the setting of systolic heart failure.
Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a condition characterized by
 intermittent partial collapse and closure of the upper airway (UA). This leads to sleep
 fragmentation, oxygen desaturation, hypercarbia, and activation of the sympathetic nervous
 system. OSAHS is also associated with excessive daytime sleepiness, as well as other
 behavioral, functional, cardiovascular and cognitive dysfunction.

 Continuous Positive Airway Pressure (CPAP) is the most effective treatment for the OSAHS.
 CPAP stabilizes the airway and prevents instability and collapse. With a stable airway,
 breathing continues in a normal manner, gas exchange is improved, and there is no disruption
 of sleep related to disturbed breathing.

 CPAP is applied to the upper airway via a mask that covers the nose or the nose and mouth and
 reduces/eliminates sleep disordered breathing. The period of maximum susceptibility to airway
 collapse is at the end of exhalation and during early inhalation. During inhalation, negative
 pressures are generated in the airway by the normal process of ventilation (increase of
 thoracic volume and reduction of intra-thoracic pressure). The constant pressure of CPAP
 supports the airway throughout the ventilatory cycle.

 In the sleep laboratory, titration of positive airway pressure is performed to determine
 effective CPAP pressures. During the procedure, the patient is instrumented for full
 polysomnography (PSG). Therapy is applied and pressure is adjusted during the course of the
 night to stabilize the upper airway and the breathing pattern. With conventional CPAP, a
 single pressure level is applied to the airway. While adequate for a majority of patients
 with obstructive sleep apnea, this static prescription will present challenges in certain
 patients and conditions.

 Other forms of positive airway pressure that are approved for the treatment of OSAHS include
 automatically adjusting CPAP (Auto CPAP), Bi-level Positive Airway Pressure (BiPAP), and
 automatically adjusting BiPAP. Auto CPAP evaluates the airflow pattern and adjusts pressure
 to optimize airflow. Auto CPAP accommodates patients presenting with highly variable pressure
 requirements (e.g., sleep stage or body position dependent sleep apnea). The automatic
 adjustment can be used in patients for whom in-laboratory therapy titration is either delayed
 or impossible.

 The REMStar Auto algorithm is proactive and flow-based. It evaluates the inspiratory flow and
 determines impending or actual flow limitation. This occurs in concert with a program of
 pressure adjustments designed to evaluate the pressure at which the airway is susceptible to
 collapse and maintains pressures slightly above the critical pressure. The patient is
 protected from "break-through" events with a full complement of intelligent responses to
 airflow events and snoring.

 BiPAP therapy is another alternative. With BiPAP therapy, the patient's breathing pattern is
 monitored to identify the inspiratory and expiratory phases. Pressure is increased during
 inhalation and decreased during exhalation. The expiratory pressure (EPAP) is adjusted to
 prevent airway collapse and the inspiratory pressure (IPAP) is adjusted to prevent airflow
 limitation, hypopnea, snoring or arterial desaturation not associated with complete airway
 obstruction. BiPAP therapy differs from CPAP therapy, in that in addition to stabilizing the
 airway, inspiratory effort is assisted by the difference between the inspiratory and
 expiratory pressure.

 Patients with OSAHS may be prescribed BiPAP therapy if CPAP therapy is not tolerated. BiPAP
 therapy may also be prescribed for patients with other respiratory disorders or for patients
 with both sleep and respiratory-related dysfunction.

 Patients experiencing reduced ventilation from lung disease, neuromuscular disorders, or
 problems with the control of the breathing can experience nocturnal hypoventilation that is
 worse during sleep than it is during wakefulness. These patients are typically more complex
 and require more extensive evaluation and follow-up than patients suffering only from OSAHS.
 Patients may also be more vulnerable to loss or interruptions in treatment and often require
 more advanced modes and features such as alarms and timed back-up breaths.

 OSAHS patients may respond to increases in CPAP or BiPAP therapy by demonstrating a shift in
 the nature of the apnea from obstructive to central. In these cases, patients may not receive
 adequate treatment with CPAP since lower pressure levels do not manage the instability of the
 airway leaving residual airway obstruction, while higher pressure levels are associated with
 CPAP emergent events. This condition is referred to as CPAP Emergent Complex Apnea.

 Auto SV (Auto Servo Ventilation) is a mode of positive airway pressure used to treat
 obstructive and complex central sleep apnea. Its main features include:

 -  Normalization of ventilation by automatically adjusting IPAP pressure to achieve a
 target ventilation.

 -  Provision of timed, back-up breaths during central apneas. The optimal back-up rate is
 automatically determined by the device based on the patient's breathing.

 -  Automatic control of EPAP pressure to treat obstructive events.

 Several manufacturers produce these types of devices. The algorithms used to determine the
 IPAP, EPAP and minimum respiratory rate are different. The largest number of these devices
 currently in use are the BiPAP AutoSV Advanced System One (Philips Respironics, Murrysville
 PA), Dreamstation BiPAP AutoSV and the VPAP (variable positive airway pressure) Adapt S7
 (ResMed Corp., San Diego CA).

 Adaptive Servo Ventilation (ASV) is a mode of positive airway pressure used to treat central
 sleep apnea and complex sleep apnea. The main features of the Auto SV mode include;
 normalization of ventilation by automatically adjusting IPAP to achieve and stabilize a
 target ventilation; provision of timed, back-up breaths during central apneas wherein the
 optimal back-up rate is automatically determined by the device based on the patient's
 breathing; and automatic control of EPAP to treat obstructive events.

 The older version of the VPAP Adapt (S7) was found to lead to increased risk for all-cause
 mortality when compared to control group that involved medical management in patients with
 heart failure with reduced ejection fraction and predominantly central sleep apnea in a
 recent study (SERVE-HF). An accompanying editorial by Magalang and Pack suggested that the
 device algorithms may have played a role -- specifically, greater levels of pressure assist
 and associated increase in minute ventilation. This was supported by the measurements of
 minute ventilation delivered by the S7 device in the trial which was found to be greater than
 other servo-ventilation devices. Such increased levels of ventilation could potentially cause
 respiratory alkalosis which, in turn, could lead to QT interval prolongation and cardiac
 arrhythmias. The investigators recently performed a study of patient-ventilator interaction
 in patients with complex sleep apnea and preserved cardiac contractility (left ventricular
 ejection fraction > 45%) in order to determine the performance of various ASV devices on
 respiratory parameters - such as minute ventilation and apnea-hypopnea index. In order to
 facilitate feasibility and promote safety, the investigators avoided performing the study in
 the target population of the SERVE-HF trial, viz., patients with predominant central sleep
 apnea and heart failure with reduced ejection fraction (HFreF). The investigators performed
 the study only on patients with preserved ejection fraction (LVEF > 45%). In the current
 proposal, the investigators propose to perform the study on patients with predominantly
 obstructive sleep apnea and HFreF who need ASV therapy due to PAP-emergent central apneas.

 In the prior study, in order to avoid intolerance to device therapy, the investigators
 preferred study patients who were already adherent in using servo ventilation therapy at
 home. The investigators will do the same in the currently proposed study. In the prior study,
 the investigators found that S7 device led to greater minute ventilation than other devices
 and that such greater levels of minute ventilation was attributable to a greater tidal
 volume, higher respiratory rate, and greater pressure assist. Interestingly, there was
 prolongation of QTc interval and a tendency for greater premature ventricular contractions in
 the same patients during the nights that they were exposed to the S7 device. Although the
 mechanistic basis for this finding is potentially attributable to excessive ventilation and
 related pro-arrhythmic effects of hypocapnia, the investigators had not performed measures of
 partial pressure of CO2 (PaCO2) in this prior study. Specifically, it is unclear whether
 therapy with the S7 device leads to lower PaCO2 levels than other devices and whether such
 effects are augmented in individuals with high loop gain (complex sleep apnea in the setting
 of HFreF).

 Increases in minute ventilation (Ve) during wakefulness causes hypocapnia (respiratory
 alkalosis), which, in turn, could cause hypokalemia. Hypokalemia due to nighttime
 intracellular shifts in potassium ions can prolong QT interval. Conceivably, nighttime
 alkalosis due to excessive ventilation may lead to daytime hypokalemia and QTc prolongation
 through renal loss of potassium at night with consequent effects on QTc prolongation during
 the daytime. The observed QTc prolongation during S7 therapy was small in magnitude (~ 20
 msec), but such effects may be magnified in patients with heart failure who develop metabolic
 alkalosis due to loop diuretics.The investigators did not, however, measure serum potassium
 levels which was a study limitation. In the current proposal, the investigators will
 ascertain the effects of nocturnal ASV therapy on serum potassium levels. Lastly, the
 investigators will explore the inter-individual variability in susceptibility in measured Ve
 or QTc interval.
Inclusion Criteria:

 -  Ability to provide consent

 -  Currently prescribed servo ventilation therapy at home

 -  At least two weeks of recent adherence and efficacy data from PAP device demonstrating
 adequate use of therapy (at least 4 hours of use per night and use on at least 10 of
 14 nights)

 -  Individuals with complex sleep apnea (obstructive sleep apnea with central apneas) and
 preserved left-ventricular ejection fraction (LVEF > 45%) and/or heart failure with
 preserved ejection fraction (HFrEF) who are currently on ASV therapy.

 -  Individuals with complex sleep apnea (predominantly obstructive sleep apnea with
 central apneas) and reduced left-ventricular ejection fraction (LVEF < 45%) and/or
 heart failure with reduced ejection fraction (HFrEF) who are currently on ASV therapy.

 Exclusion Criteria:

 -  Participants who are acutely ill, medically complicated or who are medically unstable

 -  Participants in whom PAP therapy is otherwise medically contraindicated

 -  Participants who are claustrophobic

 -  Symptomatic ("Symptomatic" defined as hospitalized for heart failure or a change in
 cardiac medications, within the last two months) chronic heart failure (NYHA 2-4) AND
 moderate to severe predominant central sleep apnea

 -  Participants with previously diagnosed respiratory failure or respiratory
 insufficiency and who are known to have elevated arterial carbon dioxide levels while
 awake (PaCO2 ≥ 55mmHg).

 -  Participants requiring any kind of oxygen therapy

 -  Participants who have had surgery of the upper airway, nose, sinus, eyes, or middle
 ear within the previous 90 days.