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CPAP or ASV in patients with opioid-induced SDB
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• Mogri M, et al. (2009). Hypoxemia in patients on chronic opiate therapy with and without
sleep apnea. Sleep Breath; 13: 49–57.
• Ramar K, et al. (2012). Adaptive servoventilation in patients with central or complex sleep
apnea related to chronic opioid use and congestive heart failure. J Clin Sleep Med; 8: 569–576.
• Sharkey KM, et al. (2010). Obstructive sleep apnea is more common than central sleep apnea
in methadone maintenance patients with subjective sleep complaints. Drug Alcohol Depend;
108: 77–83.
• Wang D, et al. (2007). Opioids, sleep architecture and sleep-disordered breathing. Sleep Med
Rev; 11: 35–46.
• Wasef S, et al. (2021). Treatment for patients with sleep apnea on opioids for chronic pain:
results of the OpSafe trial. J Clin Sleep Med; 17: 819–824.
• Webster LR, et al. (2008). Sleep-disordered breathing and chronic opioid therapy. Pain Med;
9: 425–432.
214
ERS Handbook: Respiratory Sleep Medicine
Treatment of central sleep
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apnoea with oxygen, drugs
and phrenic nerve stimulation
Shahrokh Javaheri and Robin Germany
In the population at large, CSA is a rare polysomnographic finding. However, in
certain populations, such as those with le ventricular dysfunction, particularly in the
presence of HF, CSA has become a common finding of PSG, as discussed elsewhere
in this book (see chapter 6.1). In this chapter, we focus on CSA therapy with various
types of medication and phrenic nerve stimulation. This is particularly relevant as
there is growing concern about the possible increase in cardiovascular death when
HF-related CSA is treated with PAP devices, such as CPAP and ASV. In the Adaptive
Servo-ventilation for CSA in Systolic HF (SERVE-HF) trial (Cowie et al., 2015), it was
hypothesised that this increase in mortality might be due to an excessive ASVassociated rise in intrathoracic pressure.
For these reasons, other CSA treatment options that are not associated with
increased intrathoracic pressure have gained considerable interest. Several medical
treatments for CSA have been attempted but data showing the promise of longterm CSA treatment are limited. In this chapter, we discuss those that aim to treat
CSA of various aetiologies. These options include oxygen (O2), pharmaceuticals and
neurostimulation.
Nocturnal low flow O2 therapy
Nocturnal O2 therapy has been exclusively studied in the treatment of CSA that is
associated with HF with reduced ejection fraction (HFrEF). This is because carotid
bodies, which mediate hypoxic chemosensitivity, are upregulated in HFrEF, resulting
in an exaggerated hypoxic response.
It has been demonstrated that the bilateral denervation of carotid bodies in patients
with HFrEF virtually eliminates the hypoxic ventilatory drive. Similarly, in rodent
models of HF, carotid body denervation normalises the altered breathing patterns.
Consistent with animal studies, both the hypoxic ventilatory response (HVR) and
the hypercapnic ventilatory response (HCVR) are augmented in patients with HFrEF.
Key points
• Non-PAP options for CSA include medication, oxygen and phrenic nerve
stimulation.
• Physicians may need multiple therapies to treat patients with both CSA
and OSA.
215ERS Handbook: Respiratory Sleep Medicine
CSA treatment with oxygen, drugs and neurostimulation
80
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n=29
p<0.0001
Javaheri
et al. (1999)
70
60
50
–1
40
AHI events·h
30
20
10
0
et al. (1989)
Room air
Oxygen
n=9
p<0.01
Hanly
n=7
p<0.05
Walsh
et al. (1995)
n=11
p=0.01
Staniforth
et al. (1998)
n=7
p=0.02
Franklin
et al. (1997)
n=22
p<0.001
Andreas
et al. (1996)
Figure 1. These studies demonstrate the ecacy of low flow oxygen therapy at night in reducing
CSA. Data presented as mean±. Reproduced and modified from Javaheri (2022) with
permission.
Several studies have shown that low flow nocturnal O2 therapy attenuates CSA in
subjects with HFrEF (figure 1). These data are consistent with experiments in naturally
sleeping dogs, which showed that carotid body denervation eliminates hypocapniainduced CSA (Nakayama et al., 2003).
In parallel with attenuation of CSA, low flow nocturnal O2 therapy has been shown to
decrease augmented sympathetic activity, similar to carotid body denervation in humans
with HFrEF. Other studies have revealed improvement in maximum O2 consumption
with exercise and increased le ventricular ejection fraction and quality of life.
For the aforementioned reasons, and because of the possible failure of PAP devices to
treat CSA, the National Heart, Lung, and Blood Institute (NHLBI) approved a phase III
randomised controlled trial (RCT), which evaluated the use of low flow nocturnal O2 for
the treatment of CSA in patients with HFrEF. The primary composite endpoint of this
multisite, pragmatic RCT, was rate of rehospitalisation and mortality. A secondary aim
of the trial was to test the hypothesis that O2 treatment improves sleep quality, quality
of life, mood and exercise capacity (ClinicalTrials.gov NCT03745898). Unfortunately,
in the face of the coronavirus disease 2019 (COVID-19) pandemic, patient recruitment
was less than expected, and the trial was terminated aer ∼100 subjects were enrolled.
Acetazolamide
Acetazolamide (ACT), a carbonic-anhydrase inhibitor which produces metabolic
acidosis, acts as a respiratory stimulant. It lowers P
between the prevailing P
eect that is referred to as decreased plant gain; and stabilises breathing. ACT has been
and the apnoeic threshold P
aCO
2
; increases the dierence
aCO
2
aCO
(the P
2
reserve), an
aCO
2
used to treat idiopathic CSA as well as CSA associated with spinal cord injury, HFrEF and
high altitude, with all aetiologies consistently showing an improvement in CSA.
216
ERS Handbook: Respiratory Sleep Medicine
CSA treatment with oxygen, drugs and neurostimulation
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In a study by White et al. (1982) involving six subjects with idiopathic CSA, aer 1 week
of therapy with ACT, PSG demonstrated a 70% reduction in total apnoeas, a significant
decrease in the number of arousals, and improved quality of sleep and daytime sleepiness
in five of the six participants. Similar results were seen a study by DeBacker et al. (1995)
involving 14 patients, who were given a single dose of ACT before bed (250 mg, 1 h
before sleep). In the only randomised, double-blind, placebo-controlled crossover study
(Javaheri 2006), 12 patients with HFrEF and severe CSA were given 3 mg·kg−1 of ACT
before bed. Aer 5 nights of treatment, the CSA index decreased significantly from 57 to
34 events·h−1 of sleep. Patients reported improved subjective perception of overall sleep
quality, feeling rested on awakening, not falling asleep unintentionally, and a reduction
in overall fatigue. Long-term studies have not been performed.
Theophylline
Like ACT, theophylline is a respiratory stimulant. It works by decreasing plant gain.
In a double-blind, randomised, placebo-controlled crossover study of 15 patients
with treated, stable systolic HF, theophylline administered orally at a therapeutic
plasma concentration of 11 µg·mL−1 (range 7–15 µg·mL−1) was shown to improve
arterial oxyhaemoglobin saturation and decrease the AHI by around 50% (Javaheri
et al., 2006). When administered at therapeutic serum concentrations, theophylline
competes with adenosine at some of its receptor sites. In the central nervous system,
adenosine is a respiratory depressant, and theophylline stimulates respiration by
competing with adenosine. It is therefore possible that an increase in ventilation
caused by the decreasing plant gain achieved with theophylline, could, in turn,
decrease CSA.
Theophylline does not increase the ventilatory response to carbon dioxide (CO2).
Long-term theophylline use in patients with HF has potential arrhythmogenic eects
and can cause phosphodiesterase inhibition. Further controlled studies are therefore
necessary to ensure the safety of theophylline. Where it is used to treat CSA, frequent
and careful follow-up is necessary.
Buspirone
Buspirone, a 5-HT1A receptor agonist, has been used to treat general anxiety
disorders. In two animal studies, 5-HT1A receptor agonists were shown to improve
CSA (Yamauchi et al., 2008, Taylor et al., 2005). In a mouse model of central apnoeas
induced by hypoxia/reoxygenation, administration of buspirone as an intraperitoneal
injection decreased central chemosensitivity to CO2, leading to ventilatory stability.
Similar results were obtained with 8-hydroxy-2-(di-n-propylamino-) tetralin, another
5-HT1A receptor agonist, in rats and piglets.
In a randomised, double-blind, placebo-controlled crossover study, buspirone was
administered orally for 1 week in 16 patients with HFrEF (Giannoni et al., 2021). 24-hour
cardiopulmonary recordings, HVR and HCVR were performed. Compared with placebo,
buspirone attenuated CO2 but not O2 chemosensitivity. In parallel with decreased CO2
chemosensitivity, there was a significant reduction in 24-h periodic breathing, AHI, the
central apnoea index and the O2 desaturation index. These results are consistent with
those of a previous study, strongly suggesting that central chemoreceptor sensitivity is
a major contributory factor to the development of CSA in HFrEF.
If confirmed by larger studies, buspirone may be considered a valid pharmacological
alternative to NIV or phrenic nerve stimulation in future patients with HF, taking
217ERS Handbook: Respiratory Sleep Medicine
CSA treatment with oxygen, drugs and neurostimulation
1-min intervals
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Oxygen stabilises
92.59087.5
2
O
saturation
218
Central apnoea events
%
0
0.5
mV
belt
Abdominal
250
Therapy o Therapy on
0
µV
–250
0
0.5
mV
–0.5
belt
Thorax
ERS Handbook: Respiratory Sleep Medicine
Airflow
Figure 2. Example of phrenic nerve stimulation therapy. 5-min segment with therapy o and then turned on (Modified from: Costanzo MR, et al., J Card Fail
2015;21:892–902).
CSA treatment with oxygen, drugs and neurostimulation
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into account the fact that it may act across the entire 24 h on awake and freely
moving patients.
Transvenous neurostimulation
At a neuromuscular level, CSA occurs when the phrenic nerves are not activated to
initiate inspiration. Phrenic nerve stimulation results in diaphragmatic stimulation
similar to normal breathing, resulting in physiological therapy of CSA.
Transvenous phrenic nerve stimulation (TPNS) is a neurostimulation system that is
fully implanted in the cardiac suite by an electrophysiologist skilled at placing advanced
pacemaker systems. It stimulates the diaphragm to eliminate CSA (figure 2). The
stimulation lead is placed in a vein close to one of the phrenic nerves (either the le
pericardiophrenic vein or the right brachiocephalic vein) to contract the diaphragm.
Typically, the device is programmed to stimulate only at night and at a rate slightly
lower than the resting respiratory rate.
In a pivotal open RCT, 151 patients with CSA of various aetiologies, including idiopathic
CSA, HFrEF, atrial fibrillation (AF) and stroke, were implanted and randomised to
stimulation or no stimulation for 6 months (Costanzo et al., 2016). Compared with
baseline, in patients with stimulation, a significant reduction was seen in the mean
AHI (from 50 to 26 events·h−1), the central apnoea index (from 32 to 6 events·h−1)
and arousal index (from 46 to 25 events·h−1), and the O2 desaturation index improved
significantly. In concert with the improvement in sleep-disordered metrics, quality of
life and daytime sleepiness also improved significantly. There were no significant
changes in these metrics in the control group.
A recent study demonstrated improvements in central events, arousals, oxygenation
and daytime sleepiness over 5 years. In another study, Potratz et al. (2020)
demonstrated improvements in a 6-min walk test (6MWT) of 40 m aer 6 months of
therapy (p=0.035).
Conclusion
Alternatives to PAP therapies are important in the treatment pathway, particularly
in patients with CSA. These alternatives include medication and phrenic nerve
stimulation. Patients may have a combination of OSA and CSA, requiring a multifaceted approach to treatment. However, large RCTs are required to define the ecacy
and safety of these approaches in the long-term.
Further reading
• Andreas S, et al. (1996). Improvement of exercise capacity with treatment of Cheyne-Stokes
respiration in patients with congestive heart failure. J Am Coll Cardiol; 27: 1486–1490.
• Bradley TD, et al. (2005). Continuous positive airway pressure for central sleep apnea and
heart failure. N Engl J Med; 353: 2025–2033.
• Costanzo MR, et al. (2016). Randomised controlled trial of transvenous neurostimulation for
central sleep apnoea. Lancet; 388: 974–982.
• Costanzo MR, et al. (2021). Transvenous phrenic nerve stimulation for treatment of central
sleep apnea: five-year safety and ecacy outcomes. Nature Sci Sleep; 13: 515–526.
• Cowie MR, et al. (2015). Adaptive servo-ventilation for central sleep apnea in systolic heart
failure. New Engl J Med; 373: 1095–1105.
219ERS Handbook: Respiratory Sleep Medicine
CSA treatment with oxygen, drugs and neurostimulation
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• DeBacker WA, et al. (1995). Central apnea index decreases aer prolonged treatment with
acetazolamide. Am J Respir Crit Care Med; 151: 87–91.
• Del Rio R, et al. (2013). Carotid chemoreceptor ablation improves survival in heart failure:
rescuing autonomic control of cardiorespiratory function. J Am Coll Cardiol; 62: 2422–2430.
• Fischer R, et al. (2004). Theophylline and acetazolamide reduce sleep-disordered breathing at
high altitude. Eur Respir J; 23: 47–52.
• Franklin KA, et al. (1997). Reversal of central sleep apnea with oxygen. Chest; 111: 163–169.
• Giannoni A, et al. (2021). Benefit of buspirone on chemoreflex and central apnoeas in heart
failure: a randomized controlled crossover trial. Eur J Heart Fail; 23: 313–320.
• Hanly PJ, et al. (1989). The eect of oxygen on respiration and sleep in patients with congestive
heart failure. Annals Int Med; 111: 777–782.
• Hu K, et al. (2003). The eect of theophylline on sleep-disordered breathing in patients with
stable chronic congestive heart failure. Chin Med J; 116: 1711–1716.
• Javaheri S (1999). A mechanism of central sleep apnea in patients with heart failure. N Engl J
Med; 341: 949–954.
• Javaheri S (2003). Pembrey’s dream: the time has come for a long-term trial of nocturnal
supplemental nasal oxygen to treat central sleep apnea in congestive heart failure. Chest; 123:
322–325.
• Javaheri S (2006). Acetazolamide improves central sleep apnea in heart failure: a double-blind
prospective study. Am J Respir Crit Care Med; 173: 234–237.
• Javaheri S (2022). Heart failure. In: Kryger MH, et al., eds Principles and Practices of Sleep
Medicine. 7th Edn. Philadelphia, WB Saunders; pp. 1462–1476.
• Javaheri S, et al. (1990). Lung function, hypoxic and hypercapnic ventilatory responses, and
respiratory muscle strength in normal subjects taking oral theophylline. Thorax; 45: 743–747.
• Javaheri S, et al. (1999). Eects of nasal O2 on sleep-related disordered breathing in ambulatory
patients with stable heart failure. Sleep; 22: 1101–1106.
• Javaheri S, et al. (2006). Eect of theophylline on sleep-disordered breathing in heart failure.
N Engl J Med; 335: 562–567.
• Javaheri S, et al. (2018). CON: Persistent central sleep apnea/Hunter-Cheyne-Stokes Breathing,
despite best guideline-based therapy of heart failure with reduced ejection fraction, is not a
compensatory mechanism and should be suppressed. J Clin Sleep Med; 14: 915–921.
• Javaheri S, et al. (2022). Central sleep apnea: pathophysiologic classification. Sleep; in press
[https://doi: 10.1093/sleep/zsac113].
• Messier ML, et al. (2004). Inhibition of medullary raphé serotonergic neurons has age-
dependent eects on the CO2 response in newborn piglets. J Appl Physiol; 96: 1909–1919.
• Nakayama H, et al. (2002). Eect of ventilatory drive on carbon dioxide sensitivity below
eupnea during sleep. Am J Respir Crit Care Med; 165: 1251–1260.
• Nakayama H, et al. (2003). Carotid body denervation eliminates apnea in response to transient
hypocapnia. J Appl Physiol; 94: 155–164.
• Niewinski P, et al. (2017). Carotid body resection for sympathetic modulation in systolic heart
failure – results from first-in-man study. Eur J Heart Fail; 19: 391–400.
• Noah J, et al. (2014). Carotid body denervation improves autonomic and cardiac function and
attenuates disordered breathing in congestive heart failure. J Physiol; 592: 391–408.
• Potratz M, et al. (2020). Phrenic nerve stimulation improves physical performance and
hypoxemia in heart failure patients with central sleep apnea. J Clin Med; 10: 202.
220
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CSA treatment with oxygen, drugs and neurostimulation
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• Sasayama S, et al. (2006). Eects of nocturnal oxygen therapy on outcome measures in
patients with chronic heart failure and Cheyne-Stokes respiration. Circ J; 70: 1–7.
• Sasayama S, et al. (2009). Improvement of quality of life with nocturnal oxygen therapy in
heart failure patients with central sleep apnea. Circ J; 73: 1255–1262.
• Sankari A, et al. (2019). Sleep-disordered breathing and spinal cord injury: a state-of-the-art
review. Chest; 155: 438–445.
• Schmick C, et al. (2020). Acetazolamide for obstructive and central sleep apnea:
a comprehensive systematic review and meta-analysis. Chest; 158: 2632–2645.
• Staniforth AD, et al. (1998). Eect of oxygen on sleep quality, cognitive function and
sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur
Heart J; 19: 922–928.
• Taylor NC, et al. (2005). Medullary serotonergic neurones modulate the ventilatory response
to hypercapnia, but not hypoxia in conscious rats. J Physiol; 566: 543–557.
• Walsh JT, et al. (1995). Eects of captopril and oxygen on sleep apnoea in patients with mild to
moderate congestive cardiac failure. Heart ; 73: 237–241.
• White DP, et al. (1982). Central sleep apnea. Improvement with acetazolamide therapy. Arch
Intern Med; 142: 1816–1819.
• Yamauchi M, et al. (2008). Eects of buspirone on posthypoxic ventilatory behavior in the
C57BL/6J and A/J mouse strains. J Appl Physiol; 105: 518–526.
221ERS Handbook: Respiratory Sleep Medicine
Treatment-emergent CSA, idiopathic CSA,
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high-altitude periodic breathing and CSA in
non-cardiac medical neurological conditions
Shahrokh Javaheri, Timothy I. Morgenthaler, Winfried Randerath
and Bernardo Selim
CSAs results from temporary pauses in the pontomedullary pacemaker, which
generates breathing rhythm. During central apnoea, there is no medullary
inspiratory neural output through the nerves innervating inspiratory thoracic pump
muscles. Therefore, polygraphically, central apnoea is characterised by the absence
of naso-oral airflow and thoracoabdominal excursions for ≥10 s. A central apnoea
index (CAI) and/or AHI ≥5 events·h−1 of sleep is considered abnormal, although
dierentiation of hypopnoeas into obstructive versus central is possible, but oen
missed in clinical practice. Therefore, some have used a CAI of ≥5 events·h−1 as
the threshold.
Definition of treatment-emergent CSA
In the ICSD-3, treatment-emergent CSA (TECSA) is grouped under CSA syndromes.
TECSA is defined by the persistence or emergence of central apnoeas and hypopnoeas
during the titration of PAP therapy without a backup respiratory rate for OSA. TECSA
should be dierentiated from other common causes of CSA (e.g. CSA with CSR or CSA
due to a medication or substance; ICSD-3) (see chapter 3.2 of this Handbook).
TECSA was first observed when OSA was treated with PAP devices without a backup
rate. However, it has also been reported following tracheostomy, oral appliance
Key points
• TECSA is the persistence or emergence of central apnoeas or hypopnoeas
following CPAP therapy for OSA, but is also seen following other therapies that
resolve upper airway obstruction.
• Similarly to TECSA, idiopathic CSA and CSA in medical and neurological
disorders result from an unstable response of the ventilatory control system
to a disturbance in ventilation (high loop gain).
• Although the majority of TECSA resolves with ongoing CPAP therapy, a
subset of patients may exhibit persistent CSA, for which ASV therapy may be
recommended.
• While the combination of acetazolamide and automatic PAP has proven
eective in HAPB, scarce data exist on the ecacy of acetazolamide or
zolpidem or PAP therapy in the other CSA conditions.
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Treatment-emergent CSA
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therapy and other surgical treatments for OSA, discussed later. For this reason, it is
best referred to as treatment-emergent CSA (TECSA). Central hypopnoeas could be
used as part of the threshold to define TECSA (i.e. central AHI ≥5 events·h−1), However,
as the dierentiation of hypopnoeas is rarely performed in routine PSG, most published
studies have used CAI ≥5 events·h−1 of sleep as the threshold.
According to a recent pathophysiological classification of CSA, TECSA falls under the
category of high loop gain mediated CSA, as described later in this chapter.
Prevalence and risk factors
In most clinical populations, CSA is significantly less common than OSA. Many initial
descriptions did not include the proviso that other known causes of CSA be excluded.
As a result, the prevalence of strictly defined TECSA is not known, but the prevalence
of CPAP-emergent CSA varies widely among dierent studies, ranging from 5% to
20%. The large variation in prevalence may be in part related to dierences in the
methodologies of these studies, including operational definitions of TECSA, protocol
designs (e.g. full-night titration versus split-night titration studies), study populations
selected (e.g. comorbid CHF or intake of opioids), dierent follow-up periods and
patient retention (table 1). In addition, studies of CPAP-emergent CSA have had
varying populations. Several studies reporting a high prevalence were split-night
studies or included patients with HF. In these three studies (Morgenthaler et al., 2006;
Dernaika et al., 2007; Lehman et al., 2007), the prevalence rates were 13%, 15% and
20%, respectively. In contrast, in studies in which full-night PSG was performed first
Table 1. Prevalence of TECSA (CAI ≥5 events·h−1)
First author;
site (year)
Morgenthaler;
Rochester,
MN, USA
(2006)
Dernaika;
Oklahoma,
OK, USA
(2007)
Lehman;
Adelaide,
Australia
(2007)
Javaheri;
Cincinnati,
OH, USA
(2009)
Endo; Japan
(2008)
Yaegashi;
Japan (2009)
Cassel;
Marburg,
Germany
(2011)
Subjects, nTECSA, % PSG AHI,
223 15 Split 23
116 20 Split 51 2
99 13 Mixed 72
1286 6.5 Full
1232 5.3 Full
297 5.7 Full
675 12.2 Full
night
night
night
night
events·h
−1
57 2
59
56
36 6.9
Follow-up
PSG, %
223ERS Handbook: Respiratory Sleep Medicine
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