Treatment-Emergent Central Sleep Apnea: A Unique Sleep-Disordered Breathing
Treatment-emergent central sleep apnea (TECSA) is a distinct form of sleep-disordered breathing characterized by the emergence or persistence of central apneas during treatment for obstructive sleep apnea (OSA). This condition, formerly known as complex sleep apnea, has garnered increasing attention due to its impact on the effectiveness of OSA treatment and patient compliance. This article provides a comprehensive overview of TECSA, including its definition, epidemiology, potential mechanisms, clinical characteristics, risk factors, and treatment options.
Definition
TECSA is defined as the appearance of central sleep apnea (CSA) or hypopnea during treatment for OSA, particularly with positive airway pressure (PAP) therapy. It was first described as “complex sleep-disordered breathing” by Gilmartin et al. and later termed “complex sleep apnea syndrome (CompSAS)” by Morgenthaler et al. The International Classification of Sleep Disorders, third edition, introduced the term TECSA to describe this phenomenon. Specifically, TECSA is diagnosed when a patient with primary OSA shows significant resolution of obstructive events during PAP therapy but exhibits a central apnea index (CAI) of ≥5 events per hour, with more than 50% of events being central. Importantly, the symptoms cannot be better explained by another CSA disorder.
TECSA has been observed not only during PAP therapy but also following other OSA treatments, such as the use of mandibular advancement devices (MAD), maxillomandibular advancement surgery, sinus and nasal surgery, and tracheostomy. In some cases, CSA events during initial continuous positive airway pressure (CPAP) titration are transient and resolve spontaneously with chronic CPAP therapy. However, in other patients, central apneas persist despite regular CPAP treatment, necessitating alternative therapeutic approaches.
Epidemiology
The prevalence of TECSA varies widely across studies, ranging from 0.56% to 20.3%. This variation is likely due to differences in study methodologies, including study design (retrospective or prospective), sample sizes, inclusion criteria, and procedures (split-night vs. full-night titration). For example, studies using full-night CPAP titration reported TECSA prevalence rates of 5.0% to 12.1%, while those using split-night polysomnography reported higher rates of 6.5% to 20.3%.
A systematic review identified nine studies on TECSA prevalence, with seven being retrospective, one prospective, and one cross-sectional. The aggregate point prevalence of TECSA was approximately 8%, with an estimated range of 5% to 20% in patients with untreated OSA. A large-scale study by Liu et al. analyzed telemonitoring data from 133,006 OSA patients and found that 3.5% of patients exhibited CSA during CPAP therapy, with CSA being transient, persistent, or emergent in 55.1%, 25.2%, and 19.7% of cases, respectively.
Certain populations, such as those with congestive heart failure (CHF) or living at high altitudes, have a higher prevalence of TECSA. For instance, Bitter et al. reported a TECSA prevalence of 18% in OSA patients with CHF, while Westhoff et al. found a prevalence of only 0.56% in OSA patients without evidence of heart failure. Additionally, studies conducted at high altitudes reported higher TECSA prevalence rates, with Pagel et al. showing rates of 10.6%, 22%, and 38.7% at altitudes of 1421, 1808, and 2165 meters, respectively.
Mechanisms
The physiological mechanisms underlying TECSA are not fully understood, but several hypotheses have been proposed. These include ventilatory control instability (high loop gain), low arousal threshold, activation of lung stretch receptors, and prolonged circulation time.
Ventilatory Control Instability (High Loop Gain):
Loop gain refers to the sensitivity of the ventilatory control system to changes in carbon dioxide (CO2) levels. Individuals with high loop gain are more prone to ventilatory instability, as they over-respond to small changes in CO2. CPAP therapy can exacerbate this instability by reducing CO2 levels below the apnea threshold, leading to central apneas. Studies have shown that patients with persistent CSA have higher loop gains than those whose CSA resolves spontaneously.
Low Arousal Threshold:
A low respiratory arousal threshold, defined as the inspiratory pressure generated just before arousal, is another potential mechanism. Frequent transitions between sleep and arousal due to a low arousal threshold can destabilize the ventilatory control system, leading to central apneas. CPAP therapy may worsen sleep quality and increase nasal resistance, further contributing to frequent arousals and central apneas.
Activation of Lung Stretch Receptors:
Over-titration of CPAP can lead to lung overexpansion, activating stretch receptors in the lungs. These receptors send inhibitory signals to the respiratory center via the vagal nerve, interrupting inspiration and causing central apneas.
Prolonged Circulation Time:
In OSA patients with CHF, prolonged circulation time can cause a mismatch between arterial blood gas levels and respiratory control, leading to central apneas. CPAP over-titration may further reduce cardiac output, exacerbating ventilatory instability.
Risk Factors and Clinical Characteristics
Several demographic, clinical, and polysomnographic factors are associated with an increased risk of TECSA. These include older age, male gender, lower body mass index (BMI), comorbid conditions (e.g., CHF, coronary artery disease, hypertension, atrial fibrillation, and stroke), chronic opioid use, and certain polysomnographic parameters such as higher baseline apnea-hypopnea index (AHI), higher baseline CAI, and higher arousal index.
Patients with TECSA are more likely to be male, older, and less severely obese. Comorbid cardiovascular and cerebrovascular diseases, particularly CHF, are significant risk factors. For example, Bitter et al. reported a TECSA prevalence of 18% in OSA patients with CHF, compared to 0.56% in those without heart failure. Additionally, long-term opioid use has been linked to CSA, although it has not been consistently identified as a risk factor for TECSA.
Treatment
CPAP Therapy:
In some patients, TECSA is self-limited, and CSA events resolve spontaneously with continued CPAP therapy. However, in others, central apneas persist, necessitating alternative treatments. Studies have shown that CSA events naturally disappear in some patients after a few months of CPAP therapy, likely due to improved ventilatory control stability and lung volume. However, CPAP is ineffective in some cases, and poor initial experiences with CPAP due to TECSA can lead to poor compliance or therapy termination.
BiPAP with a Back-Up Respiratory Rate:
Bilevel positive airway pressure with a back-up respiratory rate (BiPAP-S/T) is an effective alternative for patients who do not respond to CPAP. BiPAP-S/T provides expiratory positive airway pressure to eliminate obstructive events and inspiratory positive airway pressure with back-up ventilation to prevent hypoventilation. Studies have shown that BiPAP is superior to CPAP in treating TECSA, particularly in patients with complex sleep apnea syndrome (CompSAS).
Adaptive Servo-Ventilation (ASV):
ASV is a novel ventilatory mode that dynamically adjusts inspiratory pressure support and back-up respiratory rate based on the patient’s respiratory output. ASV is highly effective in treating TECSA, significantly reducing residual AHI and improving patient compliance. Studies have demonstrated that ASV is more effective than CPAP or BiPAP in resolving CSA events and improving symptoms in TECSA patients.
Medications:
Medications such as acetazolamide, trazodone, and eszopiclone have been explored as adjuncts to PAP therapy. Acetazolamide, a carbonic anhydrase inhibitor, can modulate loop gain and has been shown to be effective in some cases of TECSA. Trazodone and eszopiclone increase the respiratory arousal threshold, potentially reducing central apneas. However, more research is needed to confirm the effectiveness and safety of these medications.
Oxygen Therapy:
Oxygen supplementation can reduce loop gain and may be helpful in treating TECSA, particularly in patients with CHF-CSA. Short-term studies have shown that oxygen therapy reduces central respiratory events in some patients, but more evidence is needed before it can be recommended as a standard treatment for TECSA.
CO2 Supplementation:
Inhaling low concentrations of CO2 has been explored as a treatment for TECSA, as it can increase PaCO2 levels and prevent central apneas. However, concerns about safety and side effects have limited its use to experimental settings.
Future Directions
Despite significant progress in understanding TECSA, many questions remain. Large-scale epidemiological studies with rigorous designs are needed to clarify the prevalence and natural course of TECSA. Additionally, identifying specific clinical and polysomnographic predictors of TECSA development and outcomes is crucial. Further research is also needed to develop novel treatment approaches and optimize existing therapies for TECSA.
In conclusion, TECSA is a complex and heterogeneous condition that poses challenges in the treatment of OSA. Understanding its mechanisms, risk factors, and treatment options is essential for improving patient outcomes. Future studies should focus on large-scale surveys, basic scientific research, and clinical trials to address the remaining uncertainties and improve the management of TECSA.
doi.org/10.1097/CM9.0000000000001125
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