The levels of evidence (high, moderate, low, very low) and levels of recommendation (standard, guideline, option) are defined at the end of the "Major Recommendations" field.
Treatment of Central Sleep Apnea Syndrome (CSAS)
Positive airway pressure therapy may be considered for the treatment of primary CSAS. (OPTION)
Values and Trade-offs: The literature on the use of positive airway pressure (PAP) therapy (continuous positive airway pressure [CPAP], bilevel positive airway pressure in a spontaneous-timed mode [BPAP-ST], adaptive servo-ventilation [ASV]) for the treatment of primary CSAS is very limited. However, PAP therapy offers the following benefits: (1) it has the potential to ameliorate central respiratory events; (2) it typically does not confer significant risks; and (3) it is readily available in most centers. Therefore, PAP therapy can be considered for the treatment of primary CSAS. The overall very low level of quality of evidence rendered an OPTION level recommendation.
Acetazolamide has limited supporting evidence but may be considered for the treatment of primary CSAS. (OPTION)
Values and Trade-offs: Given the low overall quality of evidence and the potential for side effects including paresthesias, tinnitus, gastrointestinal symptoms, metabolic acidosis, electrolyte imbalance, and drowsiness, the use of acetazolamide for the treatment of primary CSAS received an OPTION level recommendation.
The use of zolpidem and triazolam may be considered for the treatment of primary CSAS only if the patient does not have underlying risk factors for respiratory depression. (OPTION)
Values and Trade-offs: Due to the limited available evidence and the significant potential for adverse side effects especially respiratory depression, the use of zolpidem and triazolam in the setting of primary CSAS is not a preferable option and remains the last therapeutic option, to be considered only if the other therapeutic options listed above fail. Very close clinical follow-up must be provided to consider the use of these hypnotic agents.
CSAS Due to Congestive Heart Failure (CHF) Including Cheyne Stokes Breathing Pattern (CSBP) and Not Cheyne Stokes Breathing
CPAP therapy targeted to normalize the apnea hypopnea index (AHI) is indicated for the initial treatment of CSAS related to congestive heart failure (CHF). (STANDARD)
Values and Trade-offs: The overall quality of evidence for the use of CPAP in the setting of CSAS related to CHF is moderate, but with a large effect size and consistent findings for reduction of AHI and improvement in left ventricular ejection fraction (LVEF). Post hoc analysis of the Canadian continuous positive airway pressure (CANPAP) data indicates that CPAP treatment targeted to an AHI <15 has a positive effect on transplant-free survival in patients with CSAS and CHF. Given the relative ease of availability of this therapeutic intervention and overall familiarity with its use, a STANDARD level of recommendation was given. An alternate treatment option should be considered in the absence of adequate control of CSAS related to CHF with CPAP.
BPAP therapy in a spontaneous timed (ST) mode targeted to normalize the apnea hypopnea index (AHI) may be considered for the treatment of CSAS related to CHF only if there is no response to adequate trials of CPAP, ASV, and oxygen therapies. (OPTION)
Values and Trade-offs: There were a limited number of studies that examined the effectiveness of BPAP in the treatment of CSAS/CSR. ST mode was used more frequently compared with spontaneous mode in the available studies. The level of evidence for BPAP with spontaneous mode is comprised only of 1 trial that met inclusion criteria. Therefore, no recommendation can be made for this mode of BPAP until further evidence is available. BPAP-ST therapy offers many of the same advantages as CPAP therapy, such as low risk and easy availability. BPAP-ST may be considered only in those who fail CPAP, ASV, and oxygen therapy, as these latter options have substantially more evidence supporting their use. BPAP-ST is a form of noninvasive ventilation that requires specialized expertise. The cost is approximately $1900 compared with $400-$1000 for CPAP. The paucity of data allows only an OPTION level of recommendation at this time.
Adaptive servo-ventilation (ASV) targeted to normalize the apnea-hypopnea index (AHI) is indicated for the treatment of CSAS related to CHF. (STANDARD)
Values and Tradeoff: The overall quality of evidence for ASV is moderate. While there is no survival or long-term data available for ASV at this time, there is a sufficient amount of data consistently demonstrating improvement in both the AHI and LVEF. Additionally, there was a study suggesting overall better compliance with ASV compared with CPAP. It is worth noting that most of the available studies are industry sponsored, and different manufacturers utilize different algorithms to detect respiratory events and determine characteristics of pressure delivery. Therefore, generalizability is not possible or appropriate. There is also some uncertainty as to what are the optimum settings, reflecting an overall lack of experience with using these devices. It should be mentioned that the cost of these devices is several-fold greater than the cost of CPAP, and availability is not universal. Nonetheless, the data for ASV is consistent and is at least comparable if not better than the data supporting CPAP use.
Nocturnal oxygen therapy is indicated for the treatment of CSAS related to CHF. (STANDARD)
Values and Trade-offs: Based on data presented in the original guideline document, the benefits of oxygen supplementation for the treatment of CSAS are abundant and outweigh any potential disadvantages. While the variable duration of treatment in each study limits recommendations in regard to duration of oxygen therapy, the overall positive direction of results with respect to reducing AHI and improving LVEF confirms the recommendation. Although 1 paper reported that the cumulative incidence rate of cardiac events was no different between oxygen therapy and control groups, its effect on transplant free survival has not been assessed. The universal availability of oxygen therapy coupled with the overall quality of evidence discussed above influenced the level of recommendation. It should be noted that while oxygen therapy does not confer outcome advantages over CPAP therapy in the available evidence, supplemental oxygen can be easily administered and can be given for those individuals with CSAS related to CHF who are unable to comply with CPAP therapy. Consideration should be given to a repeat sleep study with oxygen to ensure adequate resolution of central sleep apnea events. In the US, the current cost of supplemental oxygen therapy is approximately $200 per month.
The following therapies have limited supporting evidence but may be considered for the treatment of CSAS related to CHF, after optimization of standard medical therapy, if PAP therapy is not tolerated, and if accompanied by close clinical follow-up: acetazolamide and theophylline. (OPTION)
Values and Trade-offs: There is only 1 study for acetazolamide and 2 studies for theophylline. Therefore the data for each agent are very low. Furthermore, the benefits vs. harms are unclear. Side effects of acetazolamide have been previously outlined. Theophylline is also associated with a number of potential adverse effects such as cardiac arrhythmias, central nervous system (CNS) excitability, and gastrointestinal symptoms. Additionally, it has a narrow therapeutic index, and therefore close monitoring of levels is important. These pharmacological therapies require further research to generate more confidence in their effectiveness and to justify more than an OPTION level of recommendation.
CSAS Due to Medical Condition Not Cheyne Stokes: End-Stage Renal Disease (ESRD)
The following possible treatment options for CSAS related to end stage renal disease may be considered: CPAP, supplemental oxygen, bicarbonate buffer use during dialysis, and nocturnal dialysis. (OPTION)
Values and Trade-offs: At this time, the level of evidence is very low and the estimate of benefits vs. harms is unclear regarding any specific mode of therapy in end-stage renal disease (ESRD) patients with CSAS; therefore, an OPTION level of recommendation has been accorded. However, despite the very low level of evidence, it is clear that bicarbonate buffer is preferable during hemodialysis in these patients. Further studies are needed to elucidate the role of oxygen, CPAP, bicarbonate buffer use during dialysis, and nocturnal hemodialysis in patients with ESRD.
Summary of Grading of Recommendations Assessment, Development and Evaluation (GRADE) Approach to Rating Quality of Evidence*
||Initial Quality of a Body of Evidence
||Quality of a Body of Evidence
||Risk of bias
−2 Very serious
+2 Very large
|High (four plus:++++)
−2 Very serious
+1 Evidence of a gradient
|Moderate (three plus:+++O)
−2 Very serious
|All plausible residual confounding
+1 Would reduce a demonstrated effect
|Low (two plus: ++OO)
−2 Very serious
−2 Very likely
|+1 Would suggest a spurious effect if no effect was observed
||Very Low (one plus:+OOO)
Final Assessments of Level of Bodies of Evidence*
High: The guideline developers are very confident that the true effect lies close to that of the estimate of the effect.
Moderate: The guideline developers are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low: The confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low: The guideline developers have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
*From Balshem H, Helfand M, Schunemann H, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401-6.
American Academy of Sleep Medicine (AASM) Levels of Recommendations
|Final Standards of Practice Recommendations
||Overall Quality of Evidence
|Assessment of benefit/harm/burden
||Benefits clearly outweigh harm/burden
|Benefits closely balanced with harm/burden
uncertainty in the estimates of benefit/harm/burden
|Harm/burden clearly outweighs benefits