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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="para0001" class="elsevierStylePara elsevierViewall">Heart failure remains a major health challenge despite advancements in medical therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Patients with heart failure with reduced ejection fraction &#40;HFrEF&#41; often develop a form of central sleep apnoea &#40;CSA&#41; characterized by recurrent central apnoeas and hypopnoeas interposed by a prolonged crescendo -decrescendo pattern of ventilation&#44; known as Cheyne-Stokes respiration &#40;CSR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Although CSR with CSA &#40;CSR-CSA&#41; is common among patients with HFrEF&#44; it is now clear that obstructive sleep apnoea &#40;OSA&#41; is even more common in such patients&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> In patients with HFrEF&#44; OSA often presents with a prolonged crescendo-decrescendo pattern of breathing resembling CSR-CSA but with obstructive&#44; rather than central respiratory events&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> The common underlying cause of this sculpted CSR pattern is lower than normal cardiac output&#44; with prolonged time for changes in PaO<span class="elsevierStyleInf">2</span> and PaCO<span class="elsevierStyleInf">2</span> in the lungs during respiratory events to reach the peripheral and central chemoreceptors to stimulate breathing&#46; One of the reasons why both CSA and OSA are more common in patients with HFrEF than in the general population is fluid retention&#46; When upright&#44; patients with HFrEF accumulate fluid in their legs&#44; so that when lying down to sleep at night&#44; gravitation causes some of this fluid to shift to the upper body&#46; If fluid accumulates mainly in the lungs&#44; CSA may emerge due to stimulation of pulmonary vagal irritant receptors provoking hyperventilation that drives PaCO<span class="elsevierStyleInf">2</span> below the apnoea threshold&#46; If fluid collects mainly in the neck it may increase peripharyngeal tissue pressure causing the pharynx to narrow&#44; thus predisposing to obstructive events&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0002" class="elsevierStylePara elsevierViewall">Unfortunately&#44; current standard full polysomnography &#40;PSG&#41; may fall short in distinguishing central from obstructive events for at least three reasons&#46; A&#41;&#46; While oesophageal pressure detects effort&#44; standard PSG belts detect thoracic and abdominal movements&#46; In apnoeas where upper airway obstruction is present&#44; but thoraco-abdominal motion is subtle&#44; and not obviously out-of-phase&#44; it may be difficult to distinguish such obstructive events from central events in patients with HFrEF&#46; In addition&#44; nasal pressure is not helpful in distinguishing obstructive from central apnoeas because&#44; in either case&#44; there is no signal&#46; B&#41; In most patients with HFrEF&#44; and either CSA or OSA&#44; hypopnoeas rather than apnoeas predominate&#46; Differentiating obstructive from central hypopnoeas is more difficult than classifying apnoeas because thoraco-abdominal motion is present but may not be obviously out-of-phase&#46; Similarly&#44; nasal pressure tracings may not clearly demonstrate flattening as a sign of airflow limitation in the presence of upper airway obstruction&#46; C&#41; Patients with HFrEF may convert from mainly obstructive to mainly central events over a single night due to an overnight decrease in cardiac output&#44; increased lung to chemoreceptor circulation time&#44; and a fall in PaCO<span class="elsevierStyleInf">2</span> below the apnoea threshold&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a></p><p id="para0003" class="elsevierStylePara elsevierViewall">While continuous positive airway pressure &#40;CPAP&#41; is able to abolish OSA&#44; the treatment of CSR-CSA is more challenging&#46; The first large multicenter randomized trial &#40;CANPAP&#41;&#44; that evaluated the impact of CPAP in patients with HFeEF and CSR-CSA on a hard endpoint &#40;cardiovascular morbidity and mortality&#41; was neutral&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> One of the reasons may have been that CPAP only reduced the apnoea-hypopnoea index &#40;AHI&#41; by about 55&#37;&#46; However&#44; a subsequent post hoc analysis suggested a protective effect of CPAP among the sub-group of patients in whom the AHI fell below 15 events&#47;hour while on CPAP&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a></p><p id="para0004" class="elsevierStylePara elsevierViewall">Adaptive servo-ventilation &#40;ASV&#41; was designed to abolish CSR-CSA by providing variable levels of inspiratory pressure support to counteract decreases or cessation of tidal volume during central hypopnoeas and apnoeas&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> Essentially&#44; ASV stabilizes breathing by providing pressure support that is a mirror image of the patient&#180;s respiratory drive&#46; Adaptive servo-ventilation can be triggered by decrease in minute ventilation&#44; in the case of the original ResMed devices &#40;ASVmv&#41;&#44; or peak flow &#40;ASVpf&#41;&#44; in the case of the Philips devices&#46; A consistent literature showing the beneficial effects of ASV in patients with HFrEF and CSR-CSA on physiological variables<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> justified the next step&#46;</p><p id="para0005" class="elsevierStylePara elsevierViewall">The SERVE-HF trial<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> was the largest multicenter randomized trial designed to test the hypothesis that treating CSR-CSA by ASVmv in patients with HFrEF would reduce the rate of the primary composite endpoint&#58; the first event of death from any cause&#44; life-saving cardiovascular intervention&#44; or unplanned hospital admission due to worsening of HF&#46; After a median follow-up of 31 months&#44; the primary outcome was neutral&#46; However&#44; ASVmv induced an increase in all-cause and cardiovascular mortality&#46; In addition&#44; the safety of ongoing studies testing the treatment of CSR-CSA with other forms of ASV&#44; such as ASVpf&#44; was questioned&#46;<a class="elsevierStyleCrossRefs" href="#bib0011"><span class="elsevierStyleSup">11-13</span></a></p><p id="para0006" class="elsevierStylePara elsevierViewall">In this issue of Pulmonology&#44; a statement<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> by the Portuguese Society of Pulmonology and the Portuguese Sleep Association sheds light on this topic by trying to separate the wheat from the chaff&#46; The Portuguese Task Force states that the prescription of ASV plunged after the SERVE-HF publication&#46; SERVE-HF had multiple study design problems that have been described by the Portuguese Task Force and debated in several editorials&#46;<a class="elsevierStyleCrossRefs" href="#bib0011"><span class="elsevierStyleSup">11-13</span></a> The Portuguese Task Force<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> raises an important flag by pointing out that ASVmv used in SERVE-HF has a minimum pressure support of 3 cm H<span class="elsevierStyleInf">2</span>O on a background minimum expiratory pressure of 5 cm H<span class="elsevierStyleInf">2</span>O&#44; even when the patient Is hyperventilating&#44; that may accentuate hyperventilation and be harmful to the patients by amplifying alkalosis related to use of diuretics&#46; If potassium levels are also low&#44; this could facilitate development of malignant cardiac arrhythmias&#46; Another critical point was that the study was over interpreted&#46; SERVE-HF was powered to answer a specific question&#44; and the main result was neutral&#46; SERVE-HF had a large number of secondary endpoints&#46; Regulatory agencies&#44; industry and medical societies&#44; however&#44; have taken a conservative approach&#44; and stated that ASV increases cardiovascular mortality&#44; based on this secondary endpoint&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> One argument in favor of this approach is that increased cardiovascular mortality is not a trivial secondary endpoint&#46; However&#44; statistics must be interpreted with caution&#46; For instance&#44; the rate of antiarrhythmic drug use at study entry was significantly higher in the ASV group than in the control group &#40;P&#61;0&#46;005&#41; and the excess mortality in the ASVmv treated group was likely due to sudden cardiac death&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> Despite the low p value&#44; this difference must be interpreted with caution as it was not driven by a hypothesis&#46;</p><p id="para0007" class="elsevierStylePara elsevierViewall">In contrast to SERVE-HF&#44; that only recruited patients that were classified as having CSA&#44; the ADVENT-HF trial<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> is a large multicenter randomized trial that was designed to test the impact of the treatment of both OSA and CSA in patients with HFrEF&#46; Unfortunately&#44; after the results of the SERVE-HF trial were published in 2015&#44; regulatory agencies in Germany and France prohibited the ADVENT-HF trial to continue to recruit patients with CSA in their countries&#46; This was a regrettable decision for the following reasons&#46; First&#44; it overruled the data and safety monitoring committee that regularly reviewed outcomes data and clearly stated that there was no discernable safety signal&#46; Second&#44; it caused a significant decrease in recruitment of patients with CSA into the trial&#44; reducing overall enrolment&#46; Third&#44; while the fear of harming patients is legitimate for clinical practice&#44; clinical trials are designed to answer difficult clinical questions&#46; Moreover&#44; the device used in ADVENT-HF differed from that used in SERVE-HF as it is peak flow-triggered with lower default inspiratory and expiratory pressure settings&#46; While the field waits for the final results of ADVENT-HF&#44; it is important to keep clinical practice on track&#46; Adaptive servo-ventilation is still recommended in other settings&#44; for instance among patients with CSA who have heart failure with preserved ejection fraction&#44; or those with idiopathic CSA or CPAP-emergent CSA&#46; In this context&#44; the Portuguese society has taken a step forward and proposed algorithms on how to manage patients with CSA&#46;</p></span>"
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Editorial
Adaptive servo-ventilation for central sleep apnea: What are the lessons learned?
G. Lorenzi-Filhoa,
Corresponding author
geraldo.lorenzi@gmail.com

Corresponding author at: Laboratório do Sono, Divisão de Pneumologia, Instituto do Coração (InCor), Av. Dr. Enéas de Carvalho Aguiar, 44 - Pinheiros, São Paulo - SP 05403-900, Brazil.
, L.F. Dragerb, T.D. Bradleyc
a Laboratório do Sono, Divisão de Pneumologia, Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil
b Unidade de Hipertensão, Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil
c KITE Sleep Research Laboratory, University Health Network Toronto Rehabilitation Institute, and Departments of Medicine of the University Health Network Toronto General Hospital and University of Toronto, Toronto, ON, Canada
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="para0001" class="elsevierStylePara elsevierViewall">Heart failure remains a major health challenge despite advancements in medical therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Patients with heart failure with reduced ejection fraction &#40;HFrEF&#41; often develop a form of central sleep apnoea &#40;CSA&#41; characterized by recurrent central apnoeas and hypopnoeas interposed by a prolonged crescendo -decrescendo pattern of ventilation&#44; known as Cheyne-Stokes respiration &#40;CSR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Although CSR with CSA &#40;CSR-CSA&#41; is common among patients with HFrEF&#44; it is now clear that obstructive sleep apnoea &#40;OSA&#41; is even more common in such patients&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> In patients with HFrEF&#44; OSA often presents with a prolonged crescendo-decrescendo pattern of breathing resembling CSR-CSA but with obstructive&#44; rather than central respiratory events&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> The common underlying cause of this sculpted CSR pattern is lower than normal cardiac output&#44; with prolonged time for changes in PaO<span class="elsevierStyleInf">2</span> and PaCO<span class="elsevierStyleInf">2</span> in the lungs during respiratory events to reach the peripheral and central chemoreceptors to stimulate breathing&#46; One of the reasons why both CSA and OSA are more common in patients with HFrEF than in the general population is fluid retention&#46; When upright&#44; patients with HFrEF accumulate fluid in their legs&#44; so that when lying down to sleep at night&#44; gravitation causes some of this fluid to shift to the upper body&#46; If fluid accumulates mainly in the lungs&#44; CSA may emerge due to stimulation of pulmonary vagal irritant receptors provoking hyperventilation that drives PaCO<span class="elsevierStyleInf">2</span> below the apnoea threshold&#46; If fluid collects mainly in the neck it may increase peripharyngeal tissue pressure causing the pharynx to narrow&#44; thus predisposing to obstructive events&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0002" class="elsevierStylePara elsevierViewall">Unfortunately&#44; current standard full polysomnography &#40;PSG&#41; may fall short in distinguishing central from obstructive events for at least three reasons&#46; A&#41;&#46; While oesophageal pressure detects effort&#44; standard PSG belts detect thoracic and abdominal movements&#46; In apnoeas where upper airway obstruction is present&#44; but thoraco-abdominal motion is subtle&#44; and not obviously out-of-phase&#44; it may be difficult to distinguish such obstructive events from central events in patients with HFrEF&#46; In addition&#44; nasal pressure is not helpful in distinguishing obstructive from central apnoeas because&#44; in either case&#44; there is no signal&#46; B&#41; In most patients with HFrEF&#44; and either CSA or OSA&#44; hypopnoeas rather than apnoeas predominate&#46; Differentiating obstructive from central hypopnoeas is more difficult than classifying apnoeas because thoraco-abdominal motion is present but may not be obviously out-of-phase&#46; Similarly&#44; nasal pressure tracings may not clearly demonstrate flattening as a sign of airflow limitation in the presence of upper airway obstruction&#46; C&#41; Patients with HFrEF may convert from mainly obstructive to mainly central events over a single night due to an overnight decrease in cardiac output&#44; increased lung to chemoreceptor circulation time&#44; and a fall in PaCO<span class="elsevierStyleInf">2</span> below the apnoea threshold&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a></p><p id="para0003" class="elsevierStylePara elsevierViewall">While continuous positive airway pressure &#40;CPAP&#41; is able to abolish OSA&#44; the treatment of CSR-CSA is more challenging&#46; The first large multicenter randomized trial &#40;CANPAP&#41;&#44; that evaluated the impact of CPAP in patients with HFeEF and CSR-CSA on a hard endpoint &#40;cardiovascular morbidity and mortality&#41; was neutral&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> One of the reasons may have been that CPAP only reduced the apnoea-hypopnoea index &#40;AHI&#41; by about 55&#37;&#46; However&#44; a subsequent post hoc analysis suggested a protective effect of CPAP among the sub-group of patients in whom the AHI fell below 15 events&#47;hour while on CPAP&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a></p><p id="para0004" class="elsevierStylePara elsevierViewall">Adaptive servo-ventilation &#40;ASV&#41; was designed to abolish CSR-CSA by providing variable levels of inspiratory pressure support to counteract decreases or cessation of tidal volume during central hypopnoeas and apnoeas&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> Essentially&#44; ASV stabilizes breathing by providing pressure support that is a mirror image of the patient&#180;s respiratory drive&#46; Adaptive servo-ventilation can be triggered by decrease in minute ventilation&#44; in the case of the original ResMed devices &#40;ASVmv&#41;&#44; or peak flow &#40;ASVpf&#41;&#44; in the case of the Philips devices&#46; A consistent literature showing the beneficial effects of ASV in patients with HFrEF and CSR-CSA on physiological variables<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> justified the next step&#46;</p><p id="para0005" class="elsevierStylePara elsevierViewall">The SERVE-HF trial<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> was the largest multicenter randomized trial designed to test the hypothesis that treating CSR-CSA by ASVmv in patients with HFrEF would reduce the rate of the primary composite endpoint&#58; the first event of death from any cause&#44; life-saving cardiovascular intervention&#44; or unplanned hospital admission due to worsening of HF&#46; After a median follow-up of 31 months&#44; the primary outcome was neutral&#46; However&#44; ASVmv induced an increase in all-cause and cardiovascular mortality&#46; In addition&#44; the safety of ongoing studies testing the treatment of CSR-CSA with other forms of ASV&#44; such as ASVpf&#44; was questioned&#46;<a class="elsevierStyleCrossRefs" href="#bib0011"><span class="elsevierStyleSup">11-13</span></a></p><p id="para0006" class="elsevierStylePara elsevierViewall">In this issue of Pulmonology&#44; a statement<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> by the Portuguese Society of Pulmonology and the Portuguese Sleep Association sheds light on this topic by trying to separate the wheat from the chaff&#46; The Portuguese Task Force states that the prescription of ASV plunged after the SERVE-HF publication&#46; SERVE-HF had multiple study design problems that have been described by the Portuguese Task Force and debated in several editorials&#46;<a class="elsevierStyleCrossRefs" href="#bib0011"><span class="elsevierStyleSup">11-13</span></a> The Portuguese Task Force<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> raises an important flag by pointing out that ASVmv used in SERVE-HF has a minimum pressure support of 3 cm H<span class="elsevierStyleInf">2</span>O on a background minimum expiratory pressure of 5 cm H<span class="elsevierStyleInf">2</span>O&#44; even when the patient Is hyperventilating&#44; that may accentuate hyperventilation and be harmful to the patients by amplifying alkalosis related to use of diuretics&#46; If potassium levels are also low&#44; this could facilitate development of malignant cardiac arrhythmias&#46; Another critical point was that the study was over interpreted&#46; SERVE-HF was powered to answer a specific question&#44; and the main result was neutral&#46; SERVE-HF had a large number of secondary endpoints&#46; Regulatory agencies&#44; industry and medical societies&#44; however&#44; have taken a conservative approach&#44; and stated that ASV increases cardiovascular mortality&#44; based on this secondary endpoint&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> One argument in favor of this approach is that increased cardiovascular mortality is not a trivial secondary endpoint&#46; However&#44; statistics must be interpreted with caution&#46; For instance&#44; the rate of antiarrhythmic drug use at study entry was significantly higher in the ASV group than in the control group &#40;P&#61;0&#46;005&#41; and the excess mortality in the ASVmv treated group was likely due to sudden cardiac death&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> Despite the low p value&#44; this difference must be interpreted with caution as it was not driven by a hypothesis&#46;</p><p id="para0007" class="elsevierStylePara elsevierViewall">In contrast to SERVE-HF&#44; that only recruited patients that were classified as having CSA&#44; the ADVENT-HF trial<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> is a large multicenter randomized trial that was designed to test the impact of the treatment of both OSA and CSA in patients with HFrEF&#46; Unfortunately&#44; after the results of the SERVE-HF trial were published in 2015&#44; regulatory agencies in Germany and France prohibited the ADVENT-HF trial to continue to recruit patients with CSA in their countries&#46; This was a regrettable decision for the following reasons&#46; First&#44; it overruled the data and safety monitoring committee that regularly reviewed outcomes data and clearly stated that there was no discernable safety signal&#46; Second&#44; it caused a significant decrease in recruitment of patients with CSA into the trial&#44; reducing overall enrolment&#46; Third&#44; while the fear of harming patients is legitimate for clinical practice&#44; clinical trials are designed to answer difficult clinical questions&#46; Moreover&#44; the device used in ADVENT-HF differed from that used in SERVE-HF as it is peak flow-triggered with lower default inspiratory and expiratory pressure settings&#46; While the field waits for the final results of ADVENT-HF&#44; it is important to keep clinical practice on track&#46; Adaptive servo-ventilation is still recommended in other settings&#44; for instance among patients with CSA who have heart failure with preserved ejection fraction&#44; or those with idiopathic CSA or CPAP-emergent CSA&#46; In this context&#44; the Portuguese society has taken a step forward and proposed algorithms on how to manage patients with CSA&#46;</p></span>"
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Article information
ISSN: 25310437
Original language: English
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