Fundamentals of Central Sleep Apnea. Emerson Kerr RRT, RPSGT Sr. Field Marketing Manager, North America

Transcription

1 Fundamentals of Central Sleep Apnea Emerson Kerr RRT, RPSGT Sr. Field Marketing Manager, North America

2 Sleep Disordered Breathing Prevalence Estimate prevalence : 100 million world wide 1 of every 5 adults has at least mild OSA 1 of every 15 has at least moderate OSA 85-90% are undiagnosed and untreated 1. World Health Organization. Gobal surveillance, prevention and control of chronic respiratory diseases : a comprehensive approach. Geneva: WHO, Young, T, Am J Respir Crit Care Med 2002;165(9):

3 SDB: Patient population Vast majority of SDB patients typical OSA profile 80 90% OSA Central Sleep Apnea Idiopathic Central Sleep Apnea Periodic breathing (Cheyne -Stokes) Complex Sleep Apnea CPAP emergent events CSA Complex OSA 3 3.Eckert, et al. Chest. 2007; 131(2):

4 Obstructive vs Central Apneas Obstructive Sleep Apnea (OSA) Central Sleep Apnea (CSA) Collapse of pharyngeal airway Respiratory drive dysfunction Airflow Airflow Thoracic Effort Thoracic Effort Cessation of inspiratory flow > 10 seconds despite increased respiratory effort often associated with a substantial O 2 desaturation Cessation of inspiratory flow > 10 seconds and absence of respiratory effort

5 Central sleep apnea (CSA) is defined as: An apnea hypopnea index > 5 and Central apneas/hypopneas > 50% of the total apneas/hypopneas and Central apneas or hypopneas greater 5 times per hour and Symptoms of either excessive sleepiness or disrupted sleep Eckert, et al. Chest. 2007; 131(2):

6 Central Sleep Apnea Classification: Hypercapnic High sleep and waking PaCO 2 Decreased ventilatory response to hypercapnia Causes: Neuromuscular disorders ALS, Myasthenia Gravis, Gillian Barre, Muscular Dystrophy Chronic use of long-acting opioids Biot s respiration Eckert, et al. Chest. 2007; 131(2):

7 Central Sleep Apnea Classification: Non-hypercapnic Normal or low waking PaCO 2 Increased ventilator response to hypercapnia Causes: Primary or Idiopathic CSA Sleep-onset CSA Cheyne-Stokes Respiration High altitude periodic breathing Complex sleep apnea Eckert, et al. Chest. 2007; 131(2):

8 Central apnea vs Cheyne Stokes Respiration Eckert, et al. Chest. 2007; 131(2):

9 Sleep Disordered Breathing in Heart Failure Patients

10 The Pathophysiology of Heart Failure At-risk patients with risk factors Triggering event (eg, MI, arrhythmia) LV Dysfunction Worsening heart failure Initial hemodynamic response Increased vascular resistance Increased heart rate Altered renal blood flow adverse remodeling Reduced stroke volume Increased filling pressures Hemodynamic effects Compensatory mechanisms Activation of RAAS Activation of SNS Activation of proinflammatory cytokines Increased vasopressin 10 Ramani CV et al Mayo Clin Proc ; 85(2):

11 The Pathophysiology of Heart Failure Structural Changes Decreased myocardium contractility Increased preload (volume) Increased afterload (resistance) Ventricular remodeling Ventricular hypertrophy Ventricular dilation Ramani CV et al Mayo Clin Proc ; 85(2):

12 Heart Failure: Functional definition New York Heart Association (NYHA) Heart Failure Symptom Classification System NYHA Class Level of Impairment I II III IV No symptom limitation with ordinary physical activity Ordinary physical activity somewhat limited by dyspnea (e.g., longdistance walking, climbing two flights of stairs) Exercise limited by dyspnea with moderate workload (e.g., shortdistance walking, climbing one flight of stairs) Dyspnea at rest or with very little exertion ACC/AHA 2005 Guidelines for the diagnosis and management of heart failure in adults:. Circulation. 2009;119:e

13 Heart Failure: Biomarkers B-type natriuretic peptide (BNP) N-terminal probnp (NT-proBNP) Gold Standard for diagnosis and prognosis Additional biomarkers, reflecting different pathophysiological processes in the development and progression of HF are listed below Myocardial insult Neurohormonal Activation Remodeling Myocyte stretch NT-proBNP, BNP, MR-proANP Renin angiotensin system Renin, angiotensin II, aldosterone Inflammation C-reactive protein, tumor necrosis factor α, Fas, interleukins, osteoprotegerin, adiponectin Myocardial Injury Troponin T, troponin I Oxidative stress Myeloperoxidase, oxidized LDL, MR-proADM Sympathetic nervous system Norepinephrine, Chromogranin A Arginine vasopressin system Arginine vasopressin Hypertrophy/Fibrosis Matrix metalloproteinases, collagen propeptides, galectin 3, soluble ST2 Apoptosis Growth differentiation factor-15 Gaggin HK et al Biochimica et Biophysica Acta 1832 (2013)

14 SDB in Heart Failure Patients Presence of sleep-disordered breathing is recognized as one of the factors contributing to the excess morbidity and mortality in HF CSA is highly prevalent in HF: 30% to 50% of patients Respiratory instability in HF lead to the rhythmic pattern of breathing referred to as Cheyne-Stokes Respiration (CSR) Constanzo MR et al. J Am Coll Cardiol 2015; 65: 72-84

15 CSA/CSR in Heart Failure: Pathophysiology Respiratory control instability LV failure Cardiac output LV filling Pulmonary congestion lung receptors activation Central Sleep apnea Hyperventilation PaCO 2 PaO 2 PaCO 2 Chemosensitivity SNA Arousal Vasoconstriction BP HR Cardiac O 2 supply Cardiac O 2 demand Yumino & Bradley. Proc Am Thorac Soc : Bradley D & Floras JS Circulation. 2003;107:

16 Pathophysiologic Consequences of CSA in HF CSA in HF Apnea-induced hypoxia-reoxygenation Arousal-induced norepinephrine release Endothelial dysfunction Inflammation Cardiac myocyte Increased arrhythmia Sodium retention RAAS activation Vasoconstriction, platelet aggregation Smooth muscle proliferation hypertrophy and apoptosis Increased BP and myocardial oxygen demand Thrombosis Left ventricular hypertrophy Altered cardiac contractility Adverse cardiac remodeling Increased cardiac preload/afterload, Plaque rupture Progression of Heart Failure Constanzo MR et al. J Am Coll Cardiol 2015; 65: 72-84

17 CUMULATIVE MORTALITY ESTIMATE (%) Sleep Apnea in Heart Failure: Prognosis Prospective observational study N = 1, 117 hospitalized patients with acute decompensated heart failure, LVEF 45 % CSA = 47 % OSA = 31% CSA OSA no SDB MONTHS 24 MONTHS 36 MONTHS Newly diagnosed CSA or OSA are both independently associated with post-discharge mortality in patients with systolic HF who are hospitalized for ADHF Khayat R et al. Eur Heart J ;36(23):1463-9

18 Servo Ventilation for Coexisting OSA and CSA in HF patients

19 Servo ventilation: CSA in HF patients Patients with HF NYHA (class II-III) and coexisting OSA and CSA Study Design: Randomized, parallel-group, single blind 51 participants completed the study. 26 autosv group 25 CPAP group Baseline 12 months P value CPAP vs ASV CPAP asv CPAP asv CAI (events/h) 21.8 ± ± ± ± 7.8 <.05 BNP (ng/ml) ± ± ± ± <.05 AutoSV reduced the central apnea hypopnea index (CAI) and brain natriuretic protein (BNP) levels significantly more effectively as compared with CPAP Randerath et al, Chest 2012;142:440-47

20 Servo Ventilation for CSA in HF patients

21 Servo ventilation: CSA in HF patients Non-randomized, parallel-group, single-center study N = 30 Baseline characteristics similar for both groups at baseline ASV Non ASV LVEF (mean ± SD) 38.3 ± ± 12.9 NYHA Class II and III (%) AutoSV treatment reduced BNP levels Mortality Re-hospitalization rates Yoshihisa A et al, Int Heart J 2011;52:

22 Servo ventilation: CSA in HF patients AutoSV treatment after unsuccessful CPAP therapy NYHA class II and III Mean LVEF = 32.9 % n=23 Baseline 3 months P value CPAP vs ASV CPAP asv CPAP asv AHI (events/h) 23.0 ± ± ± ± 1.4 <.001 LVEF (%) 32.9 ± ± ± ± 9.1 <.001 Effective suppression of CSA by ASV may improve cardiac function in HF patients Kasai T et al. JACC:Heart Fail 2013;1(1):58-63

23 Servo ventilation: CSA in HF SERVE-HF trial International, multicenter (91), randomized, parallel-group, event-driven study N= 1325 patients, follow-up 2 years. Symptomatic chronic systolic HF (LVEF 45%) AHI 15 events/h, predominantly CSA Intervention: Optimal cardiac therapy with or without ASV (AutoSet CS ; ResMed) Primary combined end-point: Time to first event of Death from any cause, life-saving cardiovascular intervention*, or unplanned hospitalization for worsening heart failure Results No difference in primary endpoint. All-cause mortality and cardiovascular mortality significantly higher under ASV Cowie et al. NEJM 2015; 373(12):

24 SERVE-HF trial Author s summary and Conclusion Bias due to unblinded study design The study was conducted in patients who had heart failure with reduced ejection fraction, and therefore the results can NOT be generalized to patients who have heart failure with preserved ejection fraction The study results also can NOT be extrapolated to patients with predominantly obstructive sleep apnea Addition of adaptive servo-ventilation to guideline based medical treatment did not improve the outcome in patients with HFrEF and CSA despite effective control of CSA Cowie et al. NEJM 2015; 373(12):

25 The unexpected findings of the SERVE-HF trial conflict with our understanding of available literature heretofore and raise several questions regarding the methodology, analysis, and interpretation of the findings. 1. Did the selected population affect the negative outcome due to the inclusion of a subgroup that is at risk for a negative outcome with ASV treatment? Did the inclusion of higher NYHA result in a worse outcome? Did the higher use of antiarrhythmic drugs in the ASV arm play a role in the negative outcome? 2. What is the impact of low compliance and a high rate of cross-over in the control arm? 3. Can the results of the SERVE-HF trial be extrapolated to the newer generation of devices with autoepap and allow lower pressures? 4. Is there a pathophysiological mechanism that can explain the increase in mortality despite suppression of the respiratory events? W Randerath, R Khayat, M Arzt, S Javaheri Sleep Medicine 16 (2015)

26 The published results of the SERVE-HF study with its limited sensitivity analysis do NOT allow final conclusions that can be applied to the management of our patients. W Randerath, R Khayat, M Arzt, S Javaheri Sleep Medicine 16 (2015)

27 Can Respir J Nov-Dec;22(6):313. Accepted Manuscript Letter to the editor concerning: Yogasundaram and Oudit: Increased mortality associated with adaptive servo-ventilation therapy in heart failure patients with central sleep apnea in the halted SERVE-HF trial John S. Floras, MD DPhil, Alexander G. Logan, MD, T. Douglas Bradley, MD 27 Canadian Journal of Cardiology 2015 in press

28 Servo ventilation: CSA in HF The SERVE-HF publication reports only the results of treatment strategy. 29% of patients discontinued or never used ASV, while 16% of patients assigned to ASV crossed over to CPAP arm. ASV low compliance, ~ 3.4 h/ night potential reason - 76% of subjects used a full face mask 2. ASV device used has relatively high default pressures as part of its ventilation algorithm (min end-expiratory press = 5 cmh20 and min insp PS = 3 cmh20). More likely to induce hyperventilation and lower cardiac output in those with normal or low left ventricular filling pressures 3. The reason of increased mortality in the ASV group is NOT known Bradley & Floras Can Resp J Nov-Dec;22(6):313

29 SERVE-HF vs ADVENT-HF trial SERVE- HF ADVENT HF Type of SDB Predominantly CSA Non sleepy OSA (64%) Device algorithm Did not allow lower end-exp pressure and min PS (5-3 cmh2o) Lower default end-exp pressure and min PS ( 4-0 cmh2o) ASV titration Not centrally reviewed Reviewed centrally * ASV adherence 3.4 h/night > 1 hour higher* Nasal mask 15% 78% Follow up yearly 2x year DSMB Reviewed data 2x in 7 years Every 6 months *Device pressure setting prescribed by the core sleep laboratory to maintain the lowest pressures possible Bradley & Floras Can Resp J Nov-Dec;22(6):313

30 Servo ventilation: CSA in HF Irrespective of the SERVE-HF, ADVENT-HF will provide Novel data regarding the effects of treating asymptomatic OSA in patients with HF Evidence as to whether the adverse effects observed in SERVE-HF were a class effect or were device specific. Bradley & Floras Can Resp J Nov-Dec;22(6):313

31 CSA/CSR in Heart Failure Suggested PAP Therapy Protocol CSA/CSR in in heart failure Optimize medical mgmt. review echocardiogram LVEF < 45% LVEF > 45% Predominant OSA CPAP Predominant CSA/CSR Evaluate for refractory symptoms CPAP ASV ASV CPAP Developed by Prof. Dr. Winfried Randerath Ayas NT et al. AJRCCM (2): AASM (2015). "Special Safety Notice: ASV therapy for central sleep apnea patients with heart failure." Clinical trials ASV, oxygen, bilevel, Phrenic nerve stimulation

32 Complex Sleep Apnea

33 Complex Sleep Apnea Development or persistence of CSA or CSR with acute CPAP therapy in patients with predominantly OA or MA during the initial diagnostic study CPAP successfully eliminates OAH events but AHI remain elevated and sleep disruption persists due to CSA or CSR Prevalence of CompSAS: range from % Differences in prevalence data are attributed to fast CPAP titration (that may lead to higher pressures and induce central apneas) supine position sleep duration use of split-night designs intake of opioid medication ethnic differences presence of predisposing factors for chronic heart failure Verbraecken J. Breathe. 2013;9(5):

34 Complex Sleep Apnea: Alternative names CPAP-emergent CSA CPAP-persistent CSA Complicated sleep disordered breathing Many consider CompSA as a clinical subtype of CSA Verbraecken J.Breathe. 2013;9(5):

35 Pathophysiology Application of CPAP Reduction of PaCO2 below apneic threshold Development of CA Verbraecken J. Breathe. 2013;9(5):

36 Servo Ventilation to Treat Complex Sleep Apnea Dellweg D, et al. Sleep 2013;36:

37 Servo Ventilation: Complex SAS Prospective, randomized, controlled trial, parallel design N= 30, 15 patients in each group Baseline 6 weeks P value (NPPV vs asv after 6 weeks NPPV asv NPPV asv AHI (events/h) 28.6 ± ± ± ± CAI (events/h) 16.7 ± ± ± ± 1.7 <.01 ODI (events/h) 17.5 ± ± ± ± 3.4 <.01 AI (events/h) 19 ± ± ± ± 1.9 <.01 At the six-week follow-up, servo ventilation was superior to NPPV in suppressing central and obstructive events Dellweg D, et al. Sleep 2013;36:

38 Opioid Induced Central Sleep Apnea

39 Opioid Induced Central Sleep Apnea Opioids are prescribed to treat chronic pain >90% of pain management clinic patients 1 Prevalence of CSA in patients taking chronic opioids is high = 24% 2 Continuous positive airway pressure is often ineffective for treating CSA 2 1. Nicholson B & Passik, SD. South Med J 2007; 100(10): Correa D, Anesth Analg. 2015; 120(6):

40 Servo-ventilation: CSA in chronic pain patients 20 patients using chronic opioids CPAP therapy is ineffective in improving opioid-associated central sleep apnea, whereas ASV is effective CAI, events/h [VALUE] ± ± ± ± 0* baseline CPAP titration CPAP re-titration ASV *p value =0.006 Javaheri et al. J Clin Sleep Med. 2014; 10(6):

41 Servo-ventilation: CSA in Chronic Pain Patients Prospective multicenter interventional study chronic pain patients prescribed 100 morphine equivalents AHI 20 and CAI 10 Intervention: System One BiPAP autosv Advanced Follow-up visits: 1 and 3 months Shapiro CM et. al, Sleep Breath Dec;19(4):

42 Servo-ventilation: CSA in chronic pain patients Comparison of respiratory variables across diagnostic PSG and titration studies (CPAP, ASV and ASV manual (PSmin 6) p values for pairwise comparisons Diagnostic PSG (N=31) CPAP (N=31) ASV (N=31) ASV manual (Psmin 6) (N=31) Overall p value (Friedman test) CPAP vs ASV CPAP vs ASV manual (PSmin 6) ASV vs ASV manual (PSmin 6) AHI 32.5 ( ) 10.1 ( ) 1.4 ( ) 2.1 ( ) <0.001 < >0.99 CAI 6.4 ( ) 2.4 ( ) 0.0 ( ) 0.0 ( ) <0.001 <0.001 <0.001 >0.99 OAI 1.9 ( ) 2.8 ( ) 0.0 ( ) 0.0 ( ) <0.001 <0.001 <0.001 >0.99 Data are expressed as median (mean + standard deviation). The above p vcvalues for the pairwise comparisons, using the Wilcoxon signed-rand test, have undergone Bonferroni adjustment HI hypopnea index, ODI oxygen saturation index ASV significantly reduced AHI, CAI, and OAI in chronic pain patients on high doses of opioids Shapiro CM et. al, Sleep Breath Dec;19(4):

43 Periodic Respiration: Suggested PAP therapy protocol Idiopathic periodic respiration Opioid-induced sleep apnea Stroke, renal failure other co morbidities Evaluate for symptoms Optimal treatment underlying disease CPAP/BPAP ASV Developed by Prof. Dr. Winfried Randerath References: Ayas NT et al. AJRCCM (2): AASM (2015). "Special Safety Notice: ASV therapy for central sleep apnea patients with heart failure

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45 References 1. Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: Pathophysiology and treatment. Chest. 2007;131(2): Ramani GV, Uber PA, Mehra MR. Chronic heart failure: contemporary diagnosis and management. Mayo Clin. Proc. 2010;85(2): WHO. Global surveillance, prevention and control of chronic respiratory diseases : a comprehensive approach Geneva: World Health Organization; Young T, Peppard PE, Gottlieb DJ. Epidemiology of Obstructive Sleep Apnea. Am. J. Respir. Crit. Care Med. 2002;165(9): Hunt SA, Abraham WT, Chin MH, et al focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119(14):e Gaggin HK, Januzzi JL, Jr. Biomarkers and diagnostics in heart failure. Biochim. Biophys. Acta. 2013;1832(12): Costanzo MR, Khayat R, Ponikowski P, et al. Mechanisms and clinical consequences of untreated central sleep apnea in heart failure. J. Am. Coll. Cardiol. 2015;65(1): 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(23): Randerath WJ, Nothofer G, Priegnitz C, et al. Long-term auto-servoventilation or constant positive pressure in heart failure and coexisting central with obstructive sleep apnea. Chest. 2012;142(2): Yoshihisa A, Shimizu T, Owada T, et al. Adaptive servo ventilation improves cardiac dysfunction and prognosis in chronic heart failure patients with Cheyne- Stokes respiration. Int. Heart J. 2011;52(4): Kasai T, Kasagi S, Maeno K, et al. Adaptive servo-ventilation in cardiac function and neurohormonal status in patients with heart failure and central sleep apnea nonresponsive to continuous positive airway pressure. JACC Heart Fail. 2013;1(1): Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. N. Engl. J. Med. 2015;373(12): Randerath W, Khayat R, Arzt M, Javaheri S. Missing links. Sleep Med. 2015;16(12): Bradley T, Flores J, Investigators fta-h. The SERVE-HF Trial. Can. Respir. J. 2015;0(0): Floras JS, Logan AG, Bradley TD. Letter to the Editor concerning: Yogasundaram and Oudit: Increased mortality associated with adaptive servo-ventilation therapy in heart failure patients with central sleep apnea in the halted SERVE-HF trial. Can. J. Cardiol Verbraecken J. Complex sleep apnoea syndrome. Breathe. 2013;9(5): Dellweg D, Kerl J, Hoehn E, Wenzel M, Koehler D. Randomized controlled trial of noninvasive positive pressure ventilation (NPPV) versus servoventilation in patients with CPAP-induced central sleep apnea (complex sleep apnea). Sleep. 2013;36(8): Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of the prevalence, mechanisms, and perioperative considerations. Anesth. Analg. 2015;120(6): Nicholson B, Passik SD. Management of chronic noncancer pain in the primary care setting. South. Med. J. 2007;100(10): Javaheri S, Harris N, Howard J, Chung E. Adaptive servoventilation for treatment of opioid-associated central sleep apnea. J. Clin. Sleep Med. 2014;10(6): AASM. Special Safety Notice: ASV therapy for central sleep apnea patients with heart failure. 2015; Ayas NT, Patil SP, Stanchina M, Malhotra A. Treatment of Central Sleep Apnea with Adaptive Servoventilation in Chronic Heart Failure. Am. J. Respir. Crit. Care Med. 2015;192(2): Shapiro CM, Chung SA, Wylie PE, et al. Home-use servo-ventilation therapy in chronic pain patients with central sleep apnea: initial and 3-month follow-up. Sleep & breathing = Schlaf & Atmung. 2015;19(4):

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