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Commentary |

SERVE-HF: More Questions Than Answers FREE TO VIEW

Shahrokh Javaheri, MD, FCCP; Lee K. Brown, MD, FCCP; Winfried Randerath, MD; Rami Khayat, MD, FCCP
Author and Funding Information

CORRESPONDENCE TO: Shahrokh Javaheri, MD, FCCP, Sleep Laboratory, Bethesda North Hospital, 10535 Montgomery Rd, Cincinnati, OH 45242


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(4):900-904. doi:10.1016/j.chest.2015.12.021
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The recent online publication of the SERVE-HF trial that evaluated the effect of treating central sleep apnea (CSA) with an adaptive servoventilation (ASV) device in patients with heart failure and reduced ejection fraction (HFrEF) has raised serious concerns about the safety of ASV in these patients. Not only was ASV ineffective but post hoc analysis found excess cardiovascular mortality in treated patients. The authors cited as one explanation an unfounded notion that CSA is a compensatory mechanism with a protective effect in HFrEF patients. We believe that there are several possible considerations that are more likely to explain the results of SERVE-HF. In this commentary, we consider methodological issues including the use of a previous-generation ASV device that constrained therapeutic settings to choices that are no longer in wide clinical use. Patient selection, data collection, and treatment adherence as well as group crossovers were not discussed in the trial as potential confounding factors. We have developed alternative reasons that could potentially explain the results and that can be explored by post hoc analysis of the SERVE-HF data. We believe that our analysis is of critical value to the field and of particular importance to clinicians treating these patients.

The recent publication of SERVE-HF, a trial that evaluated the effect of treating Hunter-Cheyne-Stokes breathing with central sleep apnea (CSA) in patients with heart failure and reduced ejection fraction (HFrEF), has raised serious concerns about the safety of adaptive servoventilation (ASV) in this population. In addition to having no effect on the primary composite end point, post hoc analysis revealed an unexpected association between randomization to ASV and excess cardiovascular mortality. The investigators speculated that (1) CSA might represent a compensatory mechanism with protective effects in HFrEF patients and (2) excess positive intrathoracic pressure caused by ASV might have had adverse cardiovascular consequences.

In our opinion, the former hypothesis has little scientific basis and lacks experimental support. In contrast, much experimental evidence exists that hypoxia, arousals, and increased sympathetic activity consequent to CSA have adverse cardiovascular effects that are reversed with positive-airway pressure therapy.,, In addition, the post hoc analysis of the Canadian continuous positive-airway pressure therapy randomized controlled trial (CANPAP) suggested that when CSA is effectively treated, survival improves.

Our careful reading of the paper, its online supplement, and the study protocol revealed important design, data collection, and analysis concerns. We address some of these issues below.

A critical inclusion criterion was the requirement that enrolled subjects have a documented left ventricular ejection fraction (LVEF) ≤ 45%. However, a range of LVEF values from 9.0% to 71.0% in the control arm and 10.0% to 54.0% in the ASV arm are noted in Table 1 in the article. Therefore, a number of patients did not meet the inclusion criteria and had heart failure with preserved ejection fraction (HFpEF). We have been informed, however, that only a small number of patients had HFpEF (oral communication to S. J. and R. K.), in which case elimination of such patients should not change the results. Nonetheless, it is important to know whether these patients were among those with increased cardiovascular mortality because treating physicians are under the impression, based on the published trial and the safety notice, that ASV remains safe in patients with HFpEF.

We are also concerned about the possibility of additional protocol violations involving LVEF because values for this crucial parameter were missing for 126 and 130 subjects in the control and ASV cohorts, respectively, as disclosed in the legend of Table 1. Again, we have been told (oral communication to S. J. and R. K.) that ven though the actual values of LVEF were not recorded, all had LVEF less than 45%. Written confirmation of this by the investigators would be helpful in this regard.

We also note in Figure 1 of the study that 87 patients in the control arm withdrew at some point in the study (most of whom subsequently started treatment with ASV); 168 subjects in the ASV cohort discontinued this treatment at some point before study completion; 21 patients assigned to ASV never received it; and 85 patients withdrew from the ASV arm. The intention-to-treat analysis considers all of these patients in calculating mortality, possibly skewing the results (see subsequent sections regarding this and other analysis issues). Sensitivity testing that includes adherence and time of exposure to the device is critical to understanding the effect of ASV on mortality.

The particular ASV device used in SERVE-HF was a first-generation model no longer manufactured by the sponsor. This technology may have applied pressures that were too low for some patients and excessive for others, with adverse cardiovascular consequences. As detailed in a recent publication, later generations of ASV devices have incorporated important advances in technology that might have affected the ultimate results had they been used in this trial.

First, the ASV device used in SERVE-HF allows for only fixed expiratory positive airway pressure (EPAP). Data from Table 2 in the study indicate that at the baseline, on average, 20% of the apnea-hypopnea index (AHI) for both control and ASV subjects was composed of obstructive events. It is known that the phenotype of sleep-disordered breathing (SDB) may change over time from predominantly central to predominantly obstructive events. In a fluid-overload state such as heart failure (HF), the latter may largely be related to shifts in fluid status. Given the variability of the sleep apnea phenotype, the fixed EPAP might at times prove inadequate, with consequent residual SDB events. Evidence that this might have occurred in SERVE-HF is found in the large range of AHIs downloaded from the ASV devices across the months of follow-up (Table S4 in the Supplementary Appendix). Recorded AHI values at 3, 12, 24, 36, and 48 months ranged as high as 72, 51, 46, 61, and 38 events/hour and mean values were all more than 5/hour. Times below an oxyhemoglobin saturation of 90% were as high as 344, 269, 285, 291, and 278 minutes at the same respective time points, and means were all 18 minutes or higher. Clearly, this previous-generation ASV device failed to adequately control SDB in some of the subjects studied, and it is therefore surprising that the authors asserted that SDB was “well controlled.” It is conceivable that patients in whom ASV failed to suppress CSA or obstructive sleep apnea contributed to the negative primary outcome or even the excess mortality. This scenario would be similar to that which was predicted and in fact materialized in a previous unsuccessful trial of positive-pressure therapy. We also note that after the first 12 months, clinic visits with device downloads occurred only annually.

These long intervals without assessment raise the possibility that mortality in some patients may have been attributable to SDB even if the last download showed adequate control of sleep apnea. This possibility is further strengthened by the fact that the ASV device used in SERVE-HF used fixed EPAP settings, although the phenotype of SDB demonstrably changed with time. Initially, central AHI accounted for 80% of all disordered breathing events; with time, however, this percentage decreased to about 40%, meaning that on average 60% of the events were considered obstructive in nature. Given the wide range of residual AHIs reported in the Supplementary Appendix, there inevitably would have been patients who developed significant obstructive apneas not adequately suppressed by the fixed expiratory pressure of the device. When and if that occurred, the ASV device used was equipped with only one strategy for suppressing these events: progressively increasing inspiratory pressure support in an attempt to open the closed airway. Once the airway opened, the prevailing high pressures may have resulted in an excessive rise in intrathoracic pressure with consequent adverse hemodynamic effects. The current generation of ASV devices can be set to increase EPAP automatically in response to obstructive apneas, and would not have been subject to this failure mode.,

Second, the combination of the relatively low inspiratory and EPAP pressures applied by the device (mean, median, and upper 95th percentile values of EPAP < 6 cm H2O at baseline and at 12 months) along with the ubiquitous use of full face masks (76% of subjects; unknown in 9%) are of concern. Low EPAP translates into low flow rates during exhalation when most of the intentional ventilatory leak occurs; use of a face mask under these conditions may enhance CO2 rebreathing.,,, Elevated levels of CO2 accumulating during the night, particularly in patients who used the device the longest, could have led to overnight renal bicarbonate retention, with incomplete clearance during the daytime resulting in sustained metabolic alkalosis. Ordinarily, metabolic alkalosis should suppress ventilation so as to produce compensatory CO2 retention that would minimize alkalemia. However, patients with HF and pulmonary congestion experience increased ventilatory drive as a result of juxtacapillary receptor stimulation that may counter any reduction in ventilatory drive. The combination of respiratory and metabolic alkalosis is well known to be arrhythmogenic and could provoke sudden death or other adverse cardiovascular events, particularly in patients with associated hypokalemia.,, We further note that most patients were receiving diuretic therapy but less than half were treated with potassium-sparing aldosterone antagonists, increasing the likelihood that some patients may have been hypokalemic. Alkalosis with or without hypokalemia is particularly arrhythmogenic in patients receiving cardiac glycosides (22% of the ASV cohort). It is important as well that many more patients in the ASV arm were receiving antiarrhythmic drugs (19.2% vs 13.5% of control subjects) and had presumably already exhibited an arrhythmia. Finally, it has been shown that patients with HFrEF and sleep apnea are at greater risk for ventricular tachycardia when plasma alkalosis is present.

The same study demonstrated that arousal index and smoking were other predictors associated with ventricular tachycardia, neither of which appears to have been adequately addressed in SERVE-HF. Arousals related to residual disordered breathing events or inappropriate airway pressures could have increased nocturnal and diurnal sympathetic activity, adding to the risk of arrhythmias and sudden death. With respect to tobacco use in patients with HFrEF, the risk of ventricular tachycardia increased almost 10-fold in smokers compared with never-smokers. Nicotine stimulates the carotid bodies, augmenting the hyperadrenergic state of HFrEF. Several studies suggest that cigarette smoking is associated with a significant increase in the risk of life-threatening ventricular tachyarrhythmias and sudden death,, and increased mortality of patients with left ventricular systolic dysfunction. We hope that smoking status was recorded in the SERVE-HF dataset and that any relationship with survival could be analyzed in future publications by the SERVE-HF investigators.

Third, given that the authors provide no information concerning correlations between ASV pressures and outcome, it is also conceivable that in some patients excessive ventilation or pressures may have contributed to excess mortality. The ASV device used in SERVE-HF is unable to lower pressure support below a minimum mandatory level of 3 cm H2O, another drawback associated with the older technology that could have resulted in excess ventilation. Although the median EPAP was 5.5 cm H2O, values as high as 11 cm H2O were reported; similarly, the mean median inspiratory positive-airway pressure was 10 cm H2O but ranged as high as 17 cm H2O. Consequently, it is possible that some patients may have received hemodynamically significant levels of airway pressure. Excess intrathoracic pressure will impair venous return and lower ventricular preload; excess pressure will raise pulmonary vascular resistance by increasing lung volume, simultaneously augmenting right ventricular afterload and diminishing left ventricular preload. The overall effect in the setting of HFrEF may well be that of reduced cardiac output, impaired coronary blood flow, myocardial ischemia, and myocardial and electrical dysfunction, leading to nocturnal or diurnal demise. These adverse effects of increased intrathoracic pressure should have been most pronounced in patients with combined (post- and precapillary) pulmonary hypertension as a result of left heart disease. Notably, SERVE-HF enrolled a larger number of patients who were more fragile than those recruited in previous studies of patients with HFrEF; >70% of SERVE-HF subjects were New York Heart Association functional class 3 or 4. Given that higher LVEF and the least periodic breathing were associated with better outcome in the control arm may be interpreted that the sicker patients were more prone to the adverse hemodynamic effects of increased intrathoracic pressure induced by ASV. The SERVE-HF investigators may be able to address these questions by additional analyses of the echocardiogram data.

It should be emphasized that the newer-generation ASV devices incorporate improvements that could address concerns related to excess airway pressures. These include (1) permitting inspiratory pressure support (IPS) values of zero; (2) modified algorithms designed to prevent inappropriate increases in IPS by limiting the maximal rate at which the target ventilation can rise (to 0.01389 L/min/s in one such device); and (3) modified algorithms facilitating more rapid declines in IPS when pressure support requirements remain stable (eg, for 90 seconds in one device) but are significantly above the minimum IPS. Clearly, large clinical trials using the newest generations of ASV will be necessary.

Fourth, we note that adherence to ASV therapy was generally quite low, with an average usage of 3.7 hours/night overall and about 40% of patients accumulating ≤ 3 hours per night (Table S3 in the Supplementary Appendix). If the secondary analysis that demonstrated adverse cardiovascular outcomes caused by ASV is accurate, then greater adherence should also correlate with worsening of this outcome, even in those in whom ASV effectively treated sleep apnea, provided ASV pressures were not excessive to lower cardiac output. Should the reverse be true, we would call into question the accuracy of the authors’ conclusions.

The study was designed to detect a difference in primary and secondary composite end points that included mortality and readmissions. The statistical design relied on a closed testing method, in which there was no type 1 error control for any outcomes other than the composite primary end point. There was no preplanned analysis or hypothesis testing strategy for mortality in the trial design as was stated in the trial’s design paper and the final published trial. Consequently, examination of mortality as an individual end point was not planned, was subject to type 1 error, and should be treated as an exploratory analysis only.

Further subgroup analyses should be performed, which may help to support or rebut the points we have raised in this commentary. In addition, we recommend that attention be paid to the important question of whether ASV improved survival in adherent patients in whom AHI decreased below various thresholds, such as 15, 10, or 5 events/hour. Unfortunately, all such analyses will be hypothesis generating only and will in the future require testing in robust prospective trials.

As clinicians caring for large numbers of patients with HF and CSA, we urge the SERVE-HF investigators to address these questions expeditiously. At the same time, we are anxiously awaiting the results of two ongoing randomized clinical trials that may help to settle some of the issues raised by SERVE-HF: ADVENT-HF, with a planned enrollment of about 850 patients with HFrEF and either obstructive sleep apnea or CSA using an advanced technology ASV device including automatic end-expiratory titration, and the Remede device trial, enrolling approximately 150 patients with predominantly CSA. The latter is a transvenously placed phrenic nerve stimulator activating diaphragm-generating negative—not positive—intrathoracic pressure to prevent CSA., However, neither of these trials are powered to determine whether patients with CSA undergoing active intervention experience significantly better survival compared with control subjects, but a favorable effect on cardiovascular survival may nonetheless emerge. Should additional analyses of the SERVE-HF data demonstrate improved cardiovascular survival when ASV effectively suppresses SDB and adherence is adequate, the weight of evidence will demand that a definitive trial be designed to address whether effective treatment of CSA in HFrEF results in improved survival.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: S. J. has received honoraria for presentations from Philips Respironics and ResMed Corporation. He is also consultant to Respicardia. L. K. B. serves on the Polysomnography Practice Advisory Committee of the New Mexico Medical Board and chairs the New Mexico Respiratory Care Advisory Board. He has served on a focus group for Koninklijke Philips N.V/Philips Respironics and is a consultant for Considine and Associates, Inc. W. R. has received honoraria for presentations from Philips Respironics, Weinmann, and ResMed Corporation. R. K. has received research support from Philips Respironics Inc and Respicardia, Inc.

Cowie M.R. .Woehrle H. .Wegscheider K. .et al Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015;373:1095-1105 [PubMed]journal. [CrossRef] [PubMed]
 
Javaheri S. .Brown L.K. .Randerath W.J. . Clinical applications of positive airway pressure therapy with adaptive servo-ventilation: part 2. Chest. 2014;146:855-868 [PubMed]journal. [CrossRef]
 
Brown L.K. .Javaheri S. . Adaptive servo-ventilation for the treatment of central sleep apnea in congestive heart failure: What have we learned? Curr Opin Pulm Med. 2014;20:550-557 [PubMed]journal. [CrossRef] [PubMed]
 
Khayat R. .Jarjoura D. .Porter K. .et al Sleep disordered breathing and post-discharge mortality in patients with acute heart failure. Eur Heart J. 2015;36:1463-1469 [PubMed]journal. [CrossRef] [PubMed]
 
Arzt M. .Floras J.S. .Logan A.G. . CANPAP Investigatorset al Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115:3173-3180 [PubMed]journal. [CrossRef] [PubMed]
 
Cowie M.R. .Woehrle H. .Wegscheider K. .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;15:937-943 [PubMed]journal. [CrossRef] [PubMed]
 
Javaheri S. .Brown L.K. .Randerath W.J. . Positive airway pressure therapy with adaptive servoventilation: part 1: operational algorithms. Chest. 2014;146:514-523 [PubMed]journal. [CrossRef] [PubMed]
 
Ryan C.M. .Floras J.S. .Logan A.G. . CANPAP Investigatorset al Shift in sleep apnoea type in heart failure patients in the CANPAP trial. Eur Respir J. 2010;35:592-597 [PubMed]journal. [CrossRef] [PubMed]
 
Yumino D. .Redolfi S. .Ruttanaumpawan P. .et al Nocturnal rostral fluid shift: a unifying concept for the pathogenesis of obstructive and central sleep apnea in men with heart failure. Circulation. 2010;121:1598-1605 [PubMed]journal. [CrossRef] [PubMed]
 
Javaheri S. . CPAP should not be used for central sleep apnea in congestive heart failure patients. J Clin Sleep Med. 2006;2:399-402 [PubMed]journal. [PubMed]
 
Javaheri S. .Goetting M.G. .Khayat R. .Wylie P.E. .Goodwin J.L. .Parthasarathy S. . The performance of two automatic servo-ventilation devices in the treatment of central sleep apnea. Sleep. 2011;34:1693-1698 [PubMed]journal. [PubMed]
 
Ferguson G.T. .Gilmartin M. . CO2 rebreathing during BiPAP ventilatory assistance. Am J Respir Crit Care Med. 1995;151:1126-1135 [PubMed]journal. [PubMed]
 
Schettino G.P.P. .Chatmongkolchart S. .Hess D.R. .Kacmarek R.M. . Position of exhalation port and mask design affect CO2 rebreathing during noninvasive positive pressure ventilation. Crit Care Med. 2003;31:2178-2182 [PubMed]journal. [CrossRef] [PubMed]
 
Samolski D. .Calaf N. .Güell R. .Casan P. .Antón A. . Carbon dioxide rebreathing in non-invasive ventilation. Analysis of masks, expiratory ports and ventilatory modes. Monaldi Arch Chest Dis. 2008;69:114-118 [PubMed]journal. [PubMed]
 
Holanda M.A. .Reis R.C. .Winkeler G.F.P. .Fortaleza S.C. .Lima J.W. .Pereira E.D. . Influence of total face, facial and nasal masks on short-term adverse effects during noninvasive ventilation. J Bras Pneumol. 2009;35:164-173 [PubMed]journal. [PubMed]
 
Javaheri S. .Kazemi H. . Metabolic alkalosis and hypoventilation in humans. Am Rev Respir Dis. 1987;136:1011-1016 [PubMed]journal. [CrossRef] [PubMed]
 
Anderson L.E. .Henrich W.L. . Alkalemia-associated morbidity and mortality in medical and surgical patients. South Med J. 1987;80:729-733 [PubMed]journal. [CrossRef] [PubMed]
 
Shirakabe A. .Hata N. .Kobayashi N. .et al Clinical significance of acid-base balance in an emergency setting in patients with acute heart failure. J Cardiol. 2012;60:288-294 [PubMed]journal. [PubMed]
 
Brater D.C. .Morrelli H.F. . Systemic alkalosis and digitalis related arrhythmias. Acta Med Scand Suppl. 1981;647:79-85 [PubMed]journal. [PubMed]
 
Javaheri S. .Shukla R. .Wexler L. . Association of smoking, sleep apnea, and plasma alkalosis with nocturnal ventricular arrhythmias in men with systolic heart failure. Chest. 2012;141:1449-1456 [PubMed]journal. [CrossRef] [PubMed]
 
Goldenberg I. .Moss A.J. .McNitt S. . Multicenter Automatic Defibrillator Implantation Trial-II Investigatorset al Cigarette smoking and the risk of supraventricular and ventricular tachyarrhythmias in high-risk cardiac patients with implantable cardioverter defibrillators. J Cardiovasc Electrophysiol. 2006;17:931-936 [PubMed]journal. [CrossRef] [PubMed]
 
Goldenberg I. .Jonas M. .Tenenbaum A. . Bezafibrate Infarction Prevention Study Groupet al Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease. Arch Intern Med. 2003;163:2301-2305 [PubMed]journal. [CrossRef] [PubMed]
 
Suskin N. .Sheth T. .Negassa A. .Yusuf S. . Relationship of current and past smoking to mortality and morbidity in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;37:1677-1682 [PubMed]journal. [CrossRef] [PubMed]
 
National Institutes of Health. Effect of Adaptive Servo Ventilation (ASV) on Survival and Hospital Admissions in Heart Failure (ADVENT-HF).https://clinicaltrials.gov/ct2/show/NCT01128816. Accessed November 9, 2015.
 
National Institutes of Health. Respicardia, Inc. Pivotal Trial of the remedē System.https://clinicaltrials.gov/ct2/show/NCT01816776. Accessed November 9, 2015.
 
Ponikowski P. .Javaheri S. .Michalkiewicz D. .et al Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure. Eur Heart J. 2012;33:889-894 [PubMed]journal. [CrossRef] [PubMed]
 
Costanzo MR, Augostini R, Goldberg LR, Ponikowski P, Stellbrink C, Javaheri S. Design of the remedē® System Pivotal Trial: a prospective, randomized study in the use of respiratory rhythm management to treat central sleep apnea [published online ahead of print September 29, 2015].J Card Fail.http://dx.doi.org/10.1016/j.cardfail.2015.08.344.
 

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References

Cowie M.R. .Woehrle H. .Wegscheider K. .et al Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015;373:1095-1105 [PubMed]journal. [CrossRef] [PubMed]
 
Javaheri S. .Brown L.K. .Randerath W.J. . Clinical applications of positive airway pressure therapy with adaptive servo-ventilation: part 2. Chest. 2014;146:855-868 [PubMed]journal. [CrossRef]
 
Brown L.K. .Javaheri S. . Adaptive servo-ventilation for the treatment of central sleep apnea in congestive heart failure: What have we learned? Curr Opin Pulm Med. 2014;20:550-557 [PubMed]journal. [CrossRef] [PubMed]
 
Khayat R. .Jarjoura D. .Porter K. .et al Sleep disordered breathing and post-discharge mortality in patients with acute heart failure. Eur Heart J. 2015;36:1463-1469 [PubMed]journal. [CrossRef] [PubMed]
 
Arzt M. .Floras J.S. .Logan A.G. . CANPAP Investigatorset al Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115:3173-3180 [PubMed]journal. [CrossRef] [PubMed]
 
Cowie M.R. .Woehrle H. .Wegscheider K. .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;15:937-943 [PubMed]journal. [CrossRef] [PubMed]
 
Javaheri S. .Brown L.K. .Randerath W.J. . Positive airway pressure therapy with adaptive servoventilation: part 1: operational algorithms. Chest. 2014;146:514-523 [PubMed]journal. [CrossRef] [PubMed]
 
Ryan C.M. .Floras J.S. .Logan A.G. . CANPAP Investigatorset al Shift in sleep apnoea type in heart failure patients in the CANPAP trial. Eur Respir J. 2010;35:592-597 [PubMed]journal. [CrossRef] [PubMed]
 
Yumino D. .Redolfi S. .Ruttanaumpawan P. .et al Nocturnal rostral fluid shift: a unifying concept for the pathogenesis of obstructive and central sleep apnea in men with heart failure. Circulation. 2010;121:1598-1605 [PubMed]journal. [CrossRef] [PubMed]
 
Javaheri S. . CPAP should not be used for central sleep apnea in congestive heart failure patients. J Clin Sleep Med. 2006;2:399-402 [PubMed]journal. [PubMed]
 
Javaheri S. .Goetting M.G. .Khayat R. .Wylie P.E. .Goodwin J.L. .Parthasarathy S. . The performance of two automatic servo-ventilation devices in the treatment of central sleep apnea. Sleep. 2011;34:1693-1698 [PubMed]journal. [PubMed]
 
Ferguson G.T. .Gilmartin M. . CO2 rebreathing during BiPAP ventilatory assistance. Am J Respir Crit Care Med. 1995;151:1126-1135 [PubMed]journal. [PubMed]
 
Schettino G.P.P. .Chatmongkolchart S. .Hess D.R. .Kacmarek R.M. . Position of exhalation port and mask design affect CO2 rebreathing during noninvasive positive pressure ventilation. Crit Care Med. 2003;31:2178-2182 [PubMed]journal. [CrossRef] [PubMed]
 
Samolski D. .Calaf N. .Güell R. .Casan P. .Antón A. . Carbon dioxide rebreathing in non-invasive ventilation. Analysis of masks, expiratory ports and ventilatory modes. Monaldi Arch Chest Dis. 2008;69:114-118 [PubMed]journal. [PubMed]
 
Holanda M.A. .Reis R.C. .Winkeler G.F.P. .Fortaleza S.C. .Lima J.W. .Pereira E.D. . Influence of total face, facial and nasal masks on short-term adverse effects during noninvasive ventilation. J Bras Pneumol. 2009;35:164-173 [PubMed]journal. [PubMed]
 
Javaheri S. .Kazemi H. . Metabolic alkalosis and hypoventilation in humans. Am Rev Respir Dis. 1987;136:1011-1016 [PubMed]journal. [CrossRef] [PubMed]
 
Anderson L.E. .Henrich W.L. . Alkalemia-associated morbidity and mortality in medical and surgical patients. South Med J. 1987;80:729-733 [PubMed]journal. [CrossRef] [PubMed]
 
Shirakabe A. .Hata N. .Kobayashi N. .et al Clinical significance of acid-base balance in an emergency setting in patients with acute heart failure. J Cardiol. 2012;60:288-294 [PubMed]journal. [PubMed]
 
Brater D.C. .Morrelli H.F. . Systemic alkalosis and digitalis related arrhythmias. Acta Med Scand Suppl. 1981;647:79-85 [PubMed]journal. [PubMed]
 
Javaheri S. .Shukla R. .Wexler L. . Association of smoking, sleep apnea, and plasma alkalosis with nocturnal ventricular arrhythmias in men with systolic heart failure. Chest. 2012;141:1449-1456 [PubMed]journal. [CrossRef] [PubMed]
 
Goldenberg I. .Moss A.J. .McNitt S. . Multicenter Automatic Defibrillator Implantation Trial-II Investigatorset al Cigarette smoking and the risk of supraventricular and ventricular tachyarrhythmias in high-risk cardiac patients with implantable cardioverter defibrillators. J Cardiovasc Electrophysiol. 2006;17:931-936 [PubMed]journal. [CrossRef] [PubMed]
 
Goldenberg I. .Jonas M. .Tenenbaum A. . Bezafibrate Infarction Prevention Study Groupet al Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease. Arch Intern Med. 2003;163:2301-2305 [PubMed]journal. [CrossRef] [PubMed]
 
Suskin N. .Sheth T. .Negassa A. .Yusuf S. . Relationship of current and past smoking to mortality and morbidity in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;37:1677-1682 [PubMed]journal. [CrossRef] [PubMed]
 
National Institutes of Health. Effect of Adaptive Servo Ventilation (ASV) on Survival and Hospital Admissions in Heart Failure (ADVENT-HF).https://clinicaltrials.gov/ct2/show/NCT01128816. Accessed November 9, 2015.
 
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