Sleep Disordered Breathing - a New Category. Excellent artic

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The figures can not be copied and pasted, but good information in the text here.
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Recognition and Management of Complex Sleep-Disordered Breathing


Geoffrey S Gilmartin; Robert W Daly; Robert J Thomas

Curr Opin Pulm Med. 2005;11(6):485-493. ©2005 Lippincott Williams & Wilkins
Posted 10/27/2005

Abstract and Introduction
Abstract
Purpose of Review: The recent rapid evolution of our understanding of the mechanisms involved in control of respiration during sleep has yielded new insights to guide our care of difficult-to-treat sleep apnea patients with complex sleep-disordered breathing. This review will describe these recent advances in the literature and suggest a model for their incorporation into clinical practice.
Recent Findings: Control of respiration during sleep shows amplified instability relative to that seen during wake in these difficult patients. Baseline (eupneic) carbon dioxide levels as well as the responsiveness of the ventilatory system to changes in carbon dioxide are all-important in this relative instability. Furthermore, the instability seen during sleep varies widely across sleep states. A further refinement of our definition of stable and unstable sleep has been developed that directly informs our understanding of the control of respiration across a night of sleep.
Summary: Complex sleep-disordered breathing is a distinct form of sleep apnea. It has recognizable characteristics that are present without, and often worsened during, positive airway pressure treatment. Both sleep state stability and the behavior of the respiratory control system contribute to this complexity. It is only with a clear understanding of the factors contributing to complex sleep-disordered breathing that implementation of truly effective clinical therapy can be achieved for this disorder, which to date is poorly controlled.

Introduction
Sleep-disordered breathing has classically been defined as obstructive or central sleep apnea. This oversimplified view of the nature of sleep apnea has inadvertently led to a limitation in our clinical capacity to care for all patients with sleep-disordered breathing. This review will define the classification of complex sleep-disordered breathing, summarize new insights into the pathophysiology of complex sleep-disordered breathing and suggest a model for the incorporation of these insights into clinical practice.

Polysomnographic Phenotypes of Sleep-Disordered Breathing
Three fundamental physiologic derangements interact to create the polysomnographic characteristics of sleep-disordered breathing. They are airflow obstruction, dysregulation of respiratory control, and hypoventilation. Their relative contributions will determine the final phenotype seen polysomnographically and may be classified into three distinct categories.

Primarily Obstructive Disease
The polysomnographic morphology of obstructive disease is well known. The respiratory abnormalities range from complete cessation of airflow (apneas) and discernible reductions in airflow (hypopneas) to flow-limitation-recovery breath sequences. The duration of significant abnormality is traditionally 10 seconds or more, but the use of flow monitoring with the nasal cannula pressure transducer system can show evolution over much longer or shorter intervals. In the pediatric age groups, relatively brief events (e.g. 5 seconds) can cause significant oxygen desaturations that may last over several normal respiratory cycles. Arousals at event termination (flow recovery) and variable degrees of oxygen desaturation are noted. Major drops in nocturnal oxygen saturation are typical of apneic obstructive disease with or without hypoventilation, but severe disease can exist without significant oxygen desaturation. Carbon dioxide homeostasis in obstructive disease is characterized by transient hypercapnia or eucapnia. Conditions associated with worsening severity of events include supine body position, rapid eye movement (REM) sleep, and bedtime use of alcohol. If there are co-existing conditions that reduce ventilatory reserve, relatively severe gas exchange abnormalities may be seen with relatively mild respiratory abnormalities. The therapeutic response to positive airway pressure is usually complete, although compliance with effective therapy remains a challenge.

Primarily Control Dysfunction (Central Disease)
Central apneas and severe periodic breathing including Cheyne-Stokes respiration are readily recognizable.[1,2] More subtle forms of periodic breathing are much more difficult to characterize, and in clinical practice 'central hypopneas' are not scored. Although the AASM 1999 scoring document gives guidelines for scoring of periodic breathing, this remains a research option. In heart failure, the cycle length may be long (60 or more seconds), or much shorter (25-40 seconds) in those with preserved cardiac output.[3**] A characteristic feature of control dysfunction-related disease is a dramatic improvement during REM sleep, which is the reverse of the pattern seen in dominantly obstructive disease. Oxygen desaturations are typically less severe than in obstructive disease, and follow a stable, drop-to-drop identical, pattern of rise and descent over time as respiration oscillates. Carbon dioxide homeostasis in central disease is characterized by mild sleep hypocapnia. The therapeutic response to positive airway pressure is usually incomplete, with significant residual periodic breathing and sleep fragmentation.[4-6,7*]

Complex Sleep-Disordered Breathing: Introducing a New Practically Useful Category
Variably 'mixed' rather than pure obstructive or central ('control') patterns are common and easily recognized. Examples include mixed apneas, variable degrees of flow limitation intermixed with periodic breathing, position-dependent variability (central while not supine, obstructive when supine), stage-dependent variability (periodic breathing during non-REM (NREM) sleep and severe obstructions during REM sleep) and time of night variability. In the latter instance, what starts as clearly obstructive disease at the beginning of the night evolves into predominantly central disease by the end of the recording.[8] Direct visualization of the upper airway shows collapse at the nadir of the respiratory cycle to be common even in polysomnographic 'central' disease. The therapeutic response to positive airway pressure is variable in these cases. A recent report has clarified some of the features of more subtle forms of mixed disease. These include periodic short cycles of obstruction, minimal disease in REM sleep, and incomplete responses to positive airway pressure. Qualitative scoring of this type of disease is limited by imprecision of terms such as 'mixed apnea,' and accurate scoring of central hypopneas is impractical in routine clinical practice. The term 'complex' is used to convey the high likelihood that both obstructive and control factors are involved in creating this pattern of disease (Fig. 1).



Figure 1.
Polysomnographic recognition of complex sleep-disordered breathing in 90-second epochs. Above, polysomnogram showing the typical features of complex disease not associated with classic periodic breathing, Cheyne-Stokes respiration, or central apneas. The cycles of respiratory abnormality are short (~25 seconds) and are obstructive. Oxygen desaturations are relatively mild, perhaps in part because the events are short. The same subject during rapid eye movement (REM) sleep shows the other characteristic feature of this form of disease: minimal abnormality during REM sleep. This patient had immediate induction of central apneas during non-REM sleep by even low levels of positive airway pressure, easy control of disease in REM sleep, and required added dead space for adequate control. CO2 while the patient was awake was 38 mm Hg, and End-tidal decreased to 36 mm Hg at sleep onset. Dead space of 150 ml kept the end-tidal CO2 between 39 and 42 mm Hg. Published with permission from.[27**]



Pathophysiology of Complex Sleep-Disordered Breathing
Anatomically narrow and excessively collapsible upper airways are seen in most patients with obstructive disease. Associations include native cephalometric abnormalities, acquired soft tissue abnormalities such as enlarged tonsils, obesity, effects of androgenic hormones, dysfunctional protective upper airway reflexes, upper airway neuropathy/myopathy, and increased airway length. This contrasts with the dominant pathophysiology - dysregulation of CO2 homeostasis - in patients with complex disease. There are two types of complex disease: hypercapnic and hypocapnic. This review focuses primarily on hypocapnic complex disease. Examples of hypercapnic complex sleep-disordered breathing include central congenital hypoventilation, advanced chronic obstructive lung disease, and obesity hypoventilation, which are beyond the scope of this review.

Sleep unmasks a highly sensitive hypocapnia-induced apneic threshold, whereby apnea is initiated by small transient reductions in arterial PaCO2 below eupnea, and respiratory rhythm is not restored until PaCO2 has risen significantly above eupneic levels.[9] Two factors determine the probability that apnea will occur.[10**,11] The CO2 reserve (the difference between eupneic PaCO2 and the apneic threshold) is determined by the plant gain of the system (the ventilatory increase required to produce a given reduction in PaCO2) and the controller gain (the ventilatory responsiveness to a given change in CO2 mediated through chemoreceptors).[12,13,14**,15,16,17*] The magnitude of the change in CO2 below eupnea needed to induce apnea may vary among patients or across different situations in an individual patient. This CO2 reserve is highly labile in NREM sleep. In addition, a highly responsive chemoreceptor or an efficiently responsive ventilatory system may also predispose to central apneas by moving eupneic CO2 closer to the apnea threshold.[18-20] These oscillations in CO2 may manifest as either frank central apneas if the threshold is crossed or perhaps as central hypopneas as the apnea threshold is approached.

Both factors are important in determining the risk for the development of centrally mediated apneas, central hypopneas, and periodic breathing.[21,22**] The system's response to a given stimulus is clearly complex.[23] For example, metabolic acidosis may elicit a compensatory increase in ventilation and thus decrease PaCO2, but there is no resulting predisposition to central apnea or periodic breathing. In fact, given that the compensatory respiratory response is always less than what is needed to raise pH back to normal, the effect of metabolic acidosis is in fact to raise the CO2 reserve by substantially lowering the apnea threshold. In this regard, metabolic acidosis is actually protective against central apnea. Conversely, with metabolic alkalosis there is a compensatory rise in eupneic PaCO2 but an even greater rise in the apnea threshold, reducing the CO2 reserve and exposing the patient to periodic breathing.[24] Hypoxia narrows the CO2 reserve even though it increases respiratory drive and increases (amplifies) the respiratory responses to CO2 below eupnea.[24]

The interactions of these components of the respiratory control system determine the individual predisposition to complex sleep-disordered breathing.[25**,26] Finally, increased instability of respiratory control may contribute to the severity of phenotypically pure obstructive sleep apnea.[10**] Several reports suggest this possibility but do not specifically address abnormalities of CO2 homeostasis. The mathematics of unstable CO2 oscillations may have underestimated the destabilizing effect of the upper airway. The upper airway is in effect doing exactly the opposite of what is ideal to counteract instability - the airway is widely patent when the system is maximally eliminating CO2 and closed when respiratory effort is at its nadir. This exacerbating of the extremes of fluctuations in CO2 makes the upper airway an important accessory in perpetuating unstable behavior. The notion that complexity may be related to CO2-dependent control instability is shown by the dramatic clinical response of patients with the complexity phenotype to small increases in inhaled CO2. This has been achieved both by the use of a prototype device, the positive airway pressure gas modulator, and also by enhanced expiratory rebreathing space ('dead space').

Recognition of 'Complexity' by Time Series Analysis of Sleep Stability States
Recent investigations have demonstrated a fundamental bimodal physiologic characteristic of NREM sleep. Briefly, NREM sleep occurs in electroencephalogram (EEG) stage and power-independent stable and unstable forms. The stable form is characterized by prominent sinus arrhythmia, blood pressure dipping, stable arousal thresholds, absence of cyclic arousals or cyclic EEG activation complexes, and temporal stability of respiration, even if individual breaths demonstrate clear flow limitation. In the domain of sleep stability using the cyclic alternating pattern (CAP) NREM EEG construct, the stable state is usually characterized by non-CAP EEG. Unstable NREM sleep is characterized by periodic phasic EEG complexes, cyclic variation in heart rate, blood pressure that stays close to the waking level, reduced and variable arousal thresholds, and temporal instability of respiration. In the domain of sleep stability when the CAP NREM EEG construct is used, the stable state is usually characterized by CAP EEG. In health, the subtly periodic respiratory volume fluctuations may be barely visually discernible but occur especially at sleep onset or during transitions into and out of individual NREM cycles and close to REM sleep. In the presence of sleep-disordered breathing, these respiratory and EEG patterns are greatly amplified.

Detection of Sleep Stability by Electrocardiogram Analysis
The EEG patterns that characterize sleep show great individual and age-dependent variability. The CAP classification is somewhat arbitrary and is strongly biased by the amplitude of phasic EEG activity. We have developed a new method of characterizing sleep stability states that uses time series analysis of the electrocardiogram (ECG), extracting and mathematically combining heart rate variability and ECG-derived respiration (amplitude modulation of the R wave secondary to varying positions of the heart associated with breathing). This generates a measure of 'cardiopulmonary coupling' (Fig. 2), which allows the assessment of temporal patterns in sleep physiology that are not constrained by EEG amplitude and conventional sleep stage. Briefly, we have identified the following features: (1) NREM sleep is fundamentally bistable, and the conventional 'grade' (stages I-IV) approach to sleep debt does not reflect the behavior of the sleep system. (2) These strikingly nonoverlapping NREM sleep stability states are present within a few months of life and remain relatively stable across the lifespan. (3) Spontaneous shifts between stability states occurs independently of conventional NREM sleep stage, EEG power, and time of night, often within an NREM period. (4) NREM bistability is seen in both health and in disease, but the dichotomy is greatly amplified and visually striking in those with sleep-disordered breathing.[27**] This latter fact motivated the use of stability states seen in patients with obstructive sleep-disordered breathing to train the ECG-based sleep physiology estimator. In healthy young adults but not in those older than about 50 years, accurate visual scoring of CAP and non-CAP states is more difficult.



Figure 2.
Electrocardiogram (ECG)-derived cardiopulmonary coupling and sleep stability during healthy sleep. Sleep spectrogram demonstrating the normal profile of high- (arrow) and low-frequency cardiopulmonary coupling (HFC and LFC, respectively) across a normal night of sleep in a 28-year-old man. From above, conventional sleep stages, LFC/HFC ratios, and the spectrographic display of cardiopulmonary coupling. HFC is not dependent on conventional slow wave sleep or delta power. HFC and LFC ratios (middle) can be computed to provide significant correlations with electroencephalogram (EEG) sleep scoring in the cyclic alternating pattern (CAP) domain. HFC and LFC alternate throughout the night. Rapid eye movement (REM) sleep in health can take on HFC characteristics if respiratory modulation of ECG amplitude dominates, whereas in disease (obstructive sleep apnea), REM sleep takes on LFC characteristics. C, CAP; N, non-CAP; WR, wake/REM.



Simple (Obstructive) Compared With Complex Disease
Recognition of sleep stability states is a fundamental concept in the proposed new approach to phenotyping complexity, because the stable mode of NREM, typically characterized by stable breathing + non-CAP EEG + high-frequency cardiopulmonary coupling, blurs the utility of global respiratory abnormality indices (respiratory disturbance index [RDI], apnea hypopnea index [AHI]). Stable NREM sleep may be increased or reduced on a given night of recording and does not contribute to the RDI. With a focus on unstable NREM sleep, typically characterized by unstable breathing + low-frequency coupling + CAP EEG, spectral analysis of periodic low-frequency behaviors allows the identification of two types of low-frequency coupling: single narrow peak and multiple broad peaks.[28*] Upper airway obstruction does not allow precisely timed repetitions and oscillations of physiologic abnormality, and the event-to-event cycle time is variable. This results in multiple broad spectral peaks. Disease driven primarily by oscillating control demonstrates precise and monotonous repetitious cycles and oscillations, resulting in narrow single spectral band cardiopulmonary coupling. Similar results may be generated by the analysis of blood pressure and EEG amplitude fluctuations, but the ECG analysis has some advantages (automated, good signal-noise characteristics, simple to obtain). In complex disease, a narrow single spectral peak of low frequency cardiopulmonary coupling is present, and converts to multiple broad peaks in REM sleep (Fig. 3). The reverse never occurs.



Figure 3.
Phenotyping sleep-disordered breathing with cardiopulmonary coupling analysis. All graphs are from the low-frequency coupled zone. Rule: Single peak narrow band coupling = complex/central disease; multiple peaks broad band coupling = obstructive disease. Above left, short-cycle periodic breathing at altitude. Above right, long-cycle periodic breathing in congestive heart failure. Below left, classic obstructive sleep apnea. Below right, complex obstructive disease. Note the restricted range of oscillating frequencies relative to the patient with obstructive disease, but not quite as 'tight' as would occur with altitude or heart failure. Polysomnographically, this patient had severe obstruction (flow limitation, obstructive apneas and hypopneas, snoring) but relatively symmetric cycling, band-like oxygen desaturation profile, minimal disease in rapid eye movement sleep, and induction of relatively pure central apneas during positive airway pressure titration.



Consequences of Complexity
Patients with complex disease cannot be adequately treated with positive airway pressure. The clinical consequences of complexity are residual symptoms (fatigue, sleepiness, depressed mood) and intolerance to therapy. Using positive airway pressure in the setting of what is effectively ongoing mixed disease must be biologically uncomfortable. Pressure support to the airway can eliminate flow limitation and improve sleep breathing, but residual control dysfunction persists. Such residual dysfunction is characterized by several predictable polysomnographic features: (1) Arousals cannot be eliminated. (2) Periodic breathing is induced or increases before flow limitation can be completely eliminated. Frank central apnea may be induced. We have termed this phenomenon 'breakpoint' - before flow limitation can be eliminated, evidence of control-related instability appears or worsens with any pressure increase. A reduction of pressure results in greater obstruction. (3) Remarkable stability during REM sleep at relatively low continuous positive airway pressure secondary to the elimination of periodic breathing caused by the presence of REM sleep. (4) At times, increasing flow limitation appears with increasing periodic breathing, typically demonstrating the morphology of maximal airway collapse during the recovery phase of the periodic breathing cycle. (5) Bilevel positive airway pressure-induced worsening of instability, characterized by induction of frank central apneas and lengthening of the respiratory event cycle times, presumably by induction of further reductions in CO2. (6) Rare if any complete response to additional oxygen. These patients by this stage of titration usually have saturation percentages in the high 90s, and further improvements in oxygenation have little effect in treating the disorder.

Management of Complex Sleep-Disordered Breathing
The approach to management of complex sleep-disordered breathing is based on the following principles:

Accurate Disease Phenotyping
Scoring of conventional central apneas and periodic breathing or Cheyne-Stokes respiration captures only a small part of the pathophysiologic process.[29*] During visual polysomnogram analysis, CAP/NREM dominant disease and short symmetric cycles of respiratory abnormality in NREM sleep are useful phenotypic markers. The use of methods to characterize the timing characteristics of disease, such as the approach described with the use of cardiopulmonary coupling, is more objective. It should be recognized that complexity may appear for the first time during positive airway pressure titration.

Positive Airway Pressure Therapy
Continuous, bilevel, and adaptive forms of positive pressure ventilation may be sufficiently effective in some patients with complex disease. Careful evaluation of the methods and results of these studies show either use of unacceptable methods of respiratory monitoring (thermistors, 4% desaturation link) or significant residual disease. Moreover, pure forms of central apnea or Cheyne-Stokes respiration that benefit from adaptive pressure ventilation may be less common than was initially thought.[30-33]

Avoiding Pressure Toxicity
Patients with complex disease are sensitive to positive airway pressure, and usually flow limitation cannot be eliminated without worsening periodic breathing or inducing central apneas. An immediate worsening with bilevel ventilation may be seen, consistent with an effect of induced hypocapnia on the peripheral chemoreceptors. One approach is 'permissive flow limitation' - allowing some obstruction to persist and thus avoiding the worsening of control dysfunction.

Oxygen Supplementation
This approach has the best chance of success if indeed some desaturations are noted, and it has been used with at best moderate success in congestive heart failure. Patients may note a subjective improvement in sleep quality with the home use of additional oxygen, but placebo effects cannot be excluded.[34*,35] It is possible that sleep stability and periodic breathing are improved at a more subtle level than can be captured by conventional polysomnography, but this hypothesis remains to be proved.

Pharmacotherapy
There are two biologically plausible approaches to the use of drugs as therapies for complex sleep-disordered breathing. The first category of drugs improves periodic breathing itself and includes theophylline and acetazolamide.[36*] Adverse effects (including worsening of obstructive disease with the latter) and partial effectiveness, however, reduce their role as sole therapy, and there are no published data of assessments as add-on therapy to positive airway pressure in central disease (there seems to be no advantage to add theophylline to treatment of obstructive disease).[37] The second approach is to increase the percentage of NREM sleep that exhibits stable characteristics. This may be achieved by improving sleep hygiene and maintaining tight sleep schedules, maximizing circadian drive and bedtime match to prevent prolonged periods of sleep-onset respiratory instability, and using drugs that induce stable NREM sleep. These include drugs that modulate γ-aminobutyric acid (GABA) transmission (classic benzodiazepines, ?-1 agonists, the selective GABA-A receptor agonist gaboxadol, the neurosteroids, and the GABA transporter blocker tiagabine) and those that act on non-GABA mechanisms such as the 5-HT2c receptor (e.g. mirtazapine) and sodium oxybate. The approach is logical but remains untested. Drugs that are known to induce complex disease may be avoided if possible, such as high-dose opiates including methadone, and baclofen.

Minimizing Hypocapnia
The most critical component of any therapy for complex disease associated with CO2 dyscontrol is to minimize hypocapnia. Strategies include using the lowest pressure that allows reasonable control, avoiding modalities that destabilize (continuous and bilevel pressure may be less or more effective in individual patients; automatic continuous pressure machines should be avoided), the use of a nonvented mask, the use of enhanced expiratory rebreathing space, and controlled increases of CO2 concentrations in the inhaled air.[38]

Nonvented mask: Vented masks prevent CO2 rebreathing or even reduce physiologic dead space in the setting of positive airway pressure therapy. The use of a nonvented mask may be enough to minimize hypocapnia-induced respiratory instability during positive airway pressure titration, and it is always worth a try. The selection available for these masks is currently limited.


Enhanced expiratory rebreathing space: Dead space alone has been reported to control central sleep apnea and heart failure-related Cheyne-Stokes respiration; however, the need to use 500 to 600 ml added inspiratory volumes is not a practical long-term option, and the numerous beneficial effects of positive airway pressure are not obtained.[39] When this is used with positive airway pressure, 100 to 150 ml is sufficient, which suggests synergistic effects of the modalities (Fig. 4). There are significant differences between this form of use and dead space alone, including the following: (i) Reduced rebreathing volumes are required. (ii) Continuous washout restricts effective dead space to expiration only (inspired CO2 does not increase). (iii) There is an absolute requirement for a very tight fit of the mask. (IV) Patients do not notice the added rebreathing space, which suggests that the positive pressure support counters this respiratory sensation.


The positive airway pressure gas modulator: This experimental device provides flow-independent and precisely controlled increases in CO2 in the inspired air. It is used with positive airway pressure and provides immediate stabilization of respiratory instability (Fig. 5). When available for clinical use, it will offer an option for the use of CO2 in clinical practice for complex hypocapnic sleep-disordered breathing.[40**]




Figure 4.
Enhanced expiratory rebreathing space enhancement of positive airway pressure therapy. Above, severe central sleep apnea occurring on the application of positive airway pressure to a patient with complex disease. Both snapshots have 'dead space' added by use of a nonvented mask and additional tubing, and show a dose response that results in small increases in end-tidal CO2. With 50 ml dead space, end-tidal CO2 is 38 mm Hg, and central apneas continue; further increase of dead space to 150 ml results in an end-tidal CO2 of 43 mm Hg and complete control of disease. Biphasic positive airway pressure is 12/8 cm, spontaneous mode, throughout. Laboratory control is easier than home control, where mask leaks are inevitable. Even in the sleep laboratory, the precision of control in comparison with the PAPGAM is not possible because of leak, turbulence, and washout effects. This method does offer practical clinical benefits to patients who are otherwise unable to use positive airway pressure, and it validates the fundamental approach of hypocapnia minimization.





Figure 5.
Positive airway pressure gas modulation with CO2. Above, persistent uncontrollable sleep apnea with a distinctive periodic pattern in a patient with mixed obstructive and central sleep apnea receiving bilevel positive airway pressure ventilation 12/8 cm, spontaneous mode, plus 4 L of additional oxygen. Below, response to addition of 0.5% CO2 into the circuit using the PAPGAM, without additional oxygen. There is complete resolution of residual periodic breathing with low concentration augmentation of positive airway pressure. Published with permission from.[40**]



Value of an Integrated Approach
An integrated approach to management considers physiology-driven therapy that balances the relative roles of mechanics, sleep stability, and respiratory control in any specific patient. Severe complex disease will likely be best controlled by the use of all three approaches simultaneously. This is in keeping with recent preliminary results from the Canadian Positive Airway Pressure trial, which suggests that positive airway pressure alone may not be adequate in those with complex disease.[41**]

Conclusion
Sleep-disordered breathing exhibits dimensions of anatomic obstruction and respiratory dyscontrol that interact in complex ways with sleep. Accurate disease phenotyping is key to management, which should then follow logical physiologic principles. The importance of deranged CO2-based control mechanisms has been underestimated in clinical practice. New therapeutic approaches include regulation of CO2 kinetics during sleep and enhancing sleep stability.

References
Papers of particular interest, published within the annual period of review, have been highlighted as:

* of special interest
** of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 543-544).



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** In patients with congestive heart failure, prolonged lung-to-chemoreceptor circulation time influences the cycling characteristics of obstructive sleep apnea such that it prolongs hyperpnea and 'sculpts' in those with obstructive disease a pattern resembling Cheyne-Stokes respiration. This is an excellent example of combined pathophysiologic conditions - that is, complex disease.
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* Biventricular pacing is now a mainstream treatment for selected patients with congestive heart failure, and this report confirms that improvement of cardiac function regardless of the modality improves sleep breathing. Residual disease remains the problem, and approaches that combine modalities seem ready for clinical testing.
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** This study correlated loop gain with apnea-hypopnea index during supine NREM sleep in three groups of patients with obstructive sleep apnea on the basis of pharyngeal closing pressure: negative, atmospheric, and positive. A significant correlation was found between loop gain and apnea-hypopnea index in the atmospheric group only, which suggests that loop gain has a substantial impact on apnea severity in certain patients with sleep apnea, particularly those with a pharyngeal closing pressure near atmospheric.
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** An increase in lung water is not enough; hypocapnia is needed to induce central sleep apnea. This study is an elegant addition to the data supporting the critical role of hypocapnia in inducing nonobstructive sleep apnea syndromes.
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* Patients with central sleep apnea have a diminished cerebrovascular response to end-tidal pressure of CO2, especially to hypocapnia. Any role this has in predisposing to and maintaining complex forms of sleep apnea in clinical practice remains to be demonstrated. Data in those with complex sleep-disordered breathing without heart failure and responses to using CO2-based therapeutic strategies would be especially useful.
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Javaheri S, Almoosa KF, Saleh K, Mendenhall CL. Hypocapnia is not a predictor of central sleep apnea in patients with cirrhosis. Am J Respir Crit Care Med 2005; 171:908-911.
** The response to hypocapnia is not the same in different disease states. In patients with congestive heart failure, raised central CO2 ventilatory response predisposes to central sleep apnea, promoting background hypocapnia and exposing the apnea threshold to fluctuations in ventilation, whereas raised and faster-acting peripheral CO2 ventilatory response determines the periodicity and severity of central sleep apnea. In stroke patients, central sleep apnea is associated with hypocapnia and occult left ventricular systolic dysfunction but is not related to the location or type of stroke. In contrast to systolic heart failure, the presence of hypocapnia does not predict central sleep apnea in cirrhosis.
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** This paper is required (somewhat heavy) reading for anyone with an interest in respiratory control during sleep and its implication for clinical practice.
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** This paper describes the polysomnographic characteristics, treatment responses, and therapeutic approaches for patients with mixed/complex disease. Recognition of control dysfunction in those with apparently obstructive disease may significantly increase the percentage of patients in the sleep laboratory, where controlbased therapies may have a role.
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* This paper demonstrates that NREM sleep shows bimodal/bistable characteristics in health and disease. Sleep apnea syndromes are associated with expansion of low-frequency coupled sleep physiology as a percentage of total sleep time. Spectrographic analysis of the low-frequency band allows characterization of the relative contributions of obstruction and control physiology in the individual patient, as described in the text and figures.
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* Prolonged circulation time remains important for the induction of periodic breathing and central sleep apnea, but it is not the critical factor for the majority of those with complex sleep-disordered breathing. The cycle length is certainly modulated by circulation time (increased when longer).
Kohnlein T, Welte T, Tan LB, Elliott MW. Assisted ventilation for heart failure patients with Cheyne-Stokes respiration. Eur Respir J 2002; 20:934-941.
Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001; 164:614-619.
Pepperell JC, Maskell NA, Jones DR, et al. A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med 2003; 168:1109-1114.
Nadar S, Prasad N, Taylor RS, Lip GY. Positive pressure ventilation in the management of acute and chronic cardiac failure: a systematic review and meta-analysis. Int J Cardiol 2005; 99:171-185.
Schulz R, Fegbeutel C, Olschewski H, et al. Reversal of nocturnal periodic breathing in primary pulmonary hypertension after lung transplantation. Chest 2004; 125:344-347.
* Hypoxia-induced periodic breathing in primary pulmonary hypertension was reversed just with oxygen, but this may be a unique clinical circumstance.
Thalhofer SA, Dorow P, Meissner P. Influence of low-flow oxygen supply on sleep architecture in patients with severe heart failure (NYHA III-IV) and Cheyne-Stokes respiration. Sleep Breath 2000; 4:113-120.
Orth MM, Grootoonk S, Duchna HW, et al. Short-term effects of oral theophylline in addition to CPAP in mild to moderate OSAS. Respir Med 2005; 99:471-476.
* Oral theophylline did not show any additional effects on ventilation or pressures in patients with mild to moderate obstructive sleep apnea syndrome once continuous positive airway pressure was optimized. Patients at the obstructive end of the spectrum required no enhancement of positive airway pressure.
Hu K, Li Q, Yang J, et al. The effect of theophylline on sleep-disordered breathing in patients with stable chronic congestive heart failure. Chin Med J 2003; 116:1711-1716.
Szollosi I, Jones M, Morrell MJ, et al. Effect of CO2 inhalation on central sleep apnea and arousals from sleep. Respiration (Herrlisheim) 2004; 71:493-498.
Khayat RN, Xie A, Patel AK, et al. Cardiorespiratory effects of added dead space in patients with heart failure and central sleep apnea. Chest 2003; 123:1551-1560.
Thomas RJ, Daly RW, Weiss JW. Low concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed obstructive and central sleep-disordered breathing. Sleep 2005; 28:69-77.
** This was the first demonstration of combined use of positive airway pressure with CO2, demonstrating possible synergistic effects. The device offers a practical way to apply CO2 in the treatment of complex forms of sleep apnea. The efficacy of 0.5 to 1% CO2 and the lack of requirement to induce hypercapnia is a significant advantage. The use of positive airway pressure alone likely induces some hypocapnia in all patients, triggering instability in those so predisposed.
Bradley TD. The evidence for diagnosis and treatment of sleep disordered breathing in the heart failure patient. Scientific Symposium Presentation, Session A8, American Thoracic Society Meeting, 2005.
** The preliminary data presented showed that the application of positive airway pressure to patients with heart failure and Cheyne-Stokes respiration did not improve survival. The results on other endpoints remain to be described and published. The authors' clinical experience is that this form of therapy alone almost never obtains full control of complex sleep-disordered breathing in any clinical situation. The best therapy for this patient population may well be positive airway pressure plus gas (CO2/O2) plus γ-aminobutyric acid enhancement. This can result in nearly perfect control of disease, a prerequisite to answering questions about quality of life, cognition, and mortality.



Acknowledgements

The authors acknowledge the contribution of Joseph Mietus, who generated and provided the sleep spectograms.

Funding Information

Supported in part by NIH grant R21 HL079248 to RJT.

Abbreviation Notes

CAP = cyclic alternating pattern; ECG = electrocardiogram; EEG = electroencephalogram; GABA = γ-aminobutyric acid; NREM = non-rapid eye movement; REM = rapid eye movement

Reprint Address

Correspondence to Robert J Thomas, Division of Pulmonary, Critical Care and Sleep Medicine, CC-866, Sleep Unit, Beth Israel Deaconess Medical Center-East Campus, 330 Brookline Avenue, Boston, MA 02115, USA. Tel: 617 667 3237; fax: 617 667 4849; e-mail: rthomas1@bidmc.harvard.edu



Geoffrey S Gilmartin,a Robert W Daly,b Robert J Thomas,a

aDivision of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, and bThe Periodic Breathing Foundation, Wellesley, Massachusetts, USA

--------------------------------------------------------------------------------

[neurotransmissing]

Thanks for posting this. I need it even though I don't want to need it.

I'm sooooo confused.

I'm beginning to feel like I will never know the consequences (head injury).

The brain is so D*MN complex!

All I know is that all of this feels very overwhelming. My disorders and other conditions are due to a head injury. Diagnosis: "Progressive Neurological Damage Due to Head Trauma." But that tells me NOT MUCH! I just keep taking things one thing at a time and it's so frustrating. The good part is that it appears that the progression has peaked and ended or at least controlled for now (medications for seizures, Hashimoto's, & CPAP for SA). So it's obvious that I feel a lot of fear and don't like to look.

I did though.

Kathie

[dopey]

frequenseeker

Thanks for the posting. Sleep medicine is such a new field. Dr. DeMent has stated that it is difficult to generate scientific (e.g. grants) interest in sleeping people. There are many of us who don't respond to treatment when compliant. And perhaps some noncomliance can be due to more complex issues than simply mask discomfort and so on. So many take their masks off and don't realize it. Maybe there is a good reason for that. All my sleep studies showed PAP to have little positive effect yet all the Doc's seemed to think PAP was the therapy needed (even when the test results didn't indicate significant improvement). The bad part is that is where their (docs) interest seems to stop. If PAP doesn't do the trick, well.........just keep trying. Or so it seems to me.

[frequenseeker]

What this study seems to be saying is that some people have apnea because they are needing more carbon dioxide. The pap air works against the CO2 getting to the needed level, so apnea occurs despite the pap therapy.

This seems to really relate to my situation and I intend to look into it.

It would be good to hear from other readers here whether they get the same impression or whatever their condensed analysis of this paper may be, so more people can understand it and find it useful.

[pinetree]

I haven't gotten to read the whole article yet, but it sounds like me. I've been struggling for over a year with CPAP, APAP, BIPAP, Oxygen, pillows, tennis balls, chin straps, sleeping pills, full face masks, mandibular advancement devices, nasal lavage, aerophagia. Have been talking maybe surgery (mandible maxillary repositioning). I'm able to reduce the apnea, but not low enough to feel refreshed. Raising my pressure causes aerophagia. Using BiPAP at higher pressure helps that, but causes MORE apnea-- central apneas, like this article discusses.

At my last visit my doctor mentioned a study in Framingham Ma (where they did the famous heart research), to be extended to my town in December. I'll spend the night in the sleep lab on a BiPAP while they vary the CO2. My MD will even spend the night there monitoring things. (Probably with 6 other patients in the trials.)

My understanding is that they titrate CO2 by using a non-vented mask with a vent in the upper end of the hose, so you rebreathe some of your air, raising CO2 levels. They vary the position of the vent so you breathe more or less CO2, until the central apneas stop....


I'll post back here when I get the results.

[frequenseeker]

Pinetree - that is just what I was going to try out on myself tonight!!! I was thinking of putting tape over some of the vent holes in my Swift and see what happens. Of course, it would be completely unmonitored and I could screw myself up. But considering how screwed up I feel on bipap yet scary bad if I don't use it at all.....well, I just might do it.

When I recently used the S8 Vantage on the cpap with EPR, I got worse numbers and graphs of events, but I actually felt much better in that place that never feels right, not really a mood thing, but all I can say is it feels heavenly even if I can only get a little taste of it.

I am not far from you, I wonder if I could participate in the study. Could you contact me via my email ariwell@hotmail.com

Thanks, Pinetree

[frequenseeker]

Okay, this is the next day. I put silicone plugs (from ear protectors I got in the drug store) over half the holes in the Swift exhaust vent. I didn't have a perfect night, woke up with rainout twice as I am working out the best setting now that I am back to the integrated humidifier (do want that heated hose for Christmas!)
But basically I think there is an improvement, in my mood at least, which is one of the parameters I have noticed when I had the "better" feeling a few brief times that is my goal.
I think there is potential here. Will see how the next night goes!

[Guest]

[frequenseeker]

I am feeling better with half the Swift exhaust vents blocked. I tried adding one more blocked, but did not do well last night until I woke and took it out. Then was okay again. So I think it was too much. I had mouth leaks, curiously, and higher hypopneas.

I am learning about acidosis/alkalosis and feel there is a relationship for me with the CO2 needs.

I'll give it a few more nights and report back.

For people who have trouble with not enough CO2, the article here says apap would not be good, and I found that to be true. Good AHI, lousy feelings daytime.
There is an experimental device they refer to in the article, but not much info on it yet.

As far as I know, there is no way to continuously monitor CO2 except by drawing arterial blood gases....maybe looking at the carbonic acid in the blood would work. The article doesn't say how they did it. Oxygen is easy, with an oximeter, but CO2 can't be obtained the same way.

[deltadave]

Actually, all you need is an ETCO2 monitor such as like this one:



and you can measure end tidal carbon dioxide level continuously.
deltadave

[john57]

[deltadave]

[frequenseeker]

Delta Dave, thanks for participating in the discussion - sounds like you have some relevant background from which to contribute.

I will report the current results of my experiment:
Very Successful
I am having the second great day in a row after making my latest adjustments: I lowered the IPAP and EPAP pressures on my VPAP and continued with blocking half the vent holes in my Swift.
My AHI is 2 and I feel good!!
When I had AHI this low with the autopap trial, I felt bad, as in hung over...
I think this CO2 factor is very important in my own situation.

Could we generalize to all the folks here who have persistent hypopneas who have responded in the past to the description I have posted about such, who have said they had similar? In other words, if someone is on PAP and not feeling well and has a high hypopnea rate, or has to use a high pressure to prevent it, could they likely be in this category of CO2 problem?

[john57]

frequenseeker,

Good luck on some of your somewhat risky experiments. I am tying out some of the other mask cures that I have on my ResMed Spirit to see what differences can be made. The Dreamfit wih the lower vent rate is the only mask that I tried that gives a AHI number below one and I had two days when my AHI numbers were zero! I also have the Swift what are you using to plug the holes?

[frequenseeker]

To plug the holes, I am using silicone from ear plugs you can buy in the drug store. Works fine in terms of staying in place and providing good, reversible plug.
I don't think it is so risky, just not very precise for optimal results. The Swift has 6 holes, so you can try adding one per night if you want. I started with the three, then did four and did not feel right, feel good having gone back to the three. Someone else might need a different number.

Incidentally, the respiratory system's response of correcting acid or alkaline balance through CO2+/- is very quick, certainly quicker than the kidneys which take several days to do this. Probably this is why daytime blood gases likely wouldn't show an alteration in the CO2 values. The blood gases recover,while the kidneys suffer..?

My arterial blood gases were fine in recent test. My O2 is always very good, although perhaps that is another sign of this trouble, it was very good even when I was just starting on PAP, surprising my pulmonologist sleep doc, when I still had signs of cardiac and respiratory problems linked to SA. By the way I am not overweight and I suspect I have had SA most of my life.