Susmita Chowdhuri

The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses.

The International Classification of Sleep Disorders, Second Edition (ICSD-2) distinguishes 5 subtypes of central sleep apnea syndromes (CSAS) in adults. Review of the literature suggests that there are two basic mechanisms that trigger central respiratory events: (1) post-hyperventilation central apnea, which may be triggered by a variety of clinical conditions, and (2) central apnea secondary to hypoventilation, which has been described with opioid use. The preponderance of evidence on the treatment of CSAS supports the use of continuous positive airway pressure (CPAP). Much of the evidence comes from investigations on CSAS related to congestive heart failure (CHF), but other subtypes of CSAS appear to respond to CPAP as well. Limited evidence is available to support alternative therapies in CSAS subtypes. The recommendations for treatment of CSAS are summarized as follows: CPAP therapy targeted to normalize the apnea-hypopnea index (AHI) is indicated for the initial treatment of CSAS related to CHF. (STANDARD)Nocturnal oxygen therapy is indicated for the treatment of CSAS related to CHF. (STANDARD)Adaptive Servo-Ventilation (ASV) targeted to normalize the apnea-hypopnea index (AHI) is indicated for the treatment of CSAS related to CHF. (STANDARD)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)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)Positive airway pressure therapy may be considered for the treatment of primary CSAS. (OPTION)Acetazolamide has limited supporting evidence but may be considered for the treatment of primary CSAS. (OPTION)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)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) .

Long-term facilitation of genioglossus activity is present in normal humans during NREM sleep

UNLABELLED Episodic hypoxia (EH) is followed by increased ventilatory motor output in the recovery period indicative of long-term facilitation (LTF). We hypothesized that episodic hypoxia evokes LTF of genioglossus (GG) muscle activity in humans during non-rapid eye movement sleep (NREM) sleep. We studied 12 normal non-flow limited humans during stable NREM sleep. We induced 10 brief (3 min) episodes of isocapnic hypoxia followed by 5 min of room air. Measurements were obtained during control, hypoxia, and at 5, 10, 20, 30 and 40 min of recovery, respectively, for minute ventilation (V(I)), supraglottic pressure (P(SG)), upper airway resistance (R(UA)) and phasic GG electromyogram (EMG(GG)). In addition, sham studies were conducted on room air. During hypoxia there was a significant increase in phasic EMG(GG) (202.7+/-24.1% of control, p<0.01) and in V (I) (123.0+/-3.3% of control, p<0.05); however, only phasic EMG(GG) demonstrated a significant persistent increase throughout the recovery. (198.9+/-30.9%, 203.6+/-29.9% and 205.4+/-26.4% of control, at 5, 10, and 20 min of recovery, respectively, p<0.01). In multivariate regression analysis, age and phasic EMG(GG) activity during hypoxia were significant predictors of EMG(GG) at recovery 20 min. No significant changes in any of the measured parameters were noted during sham studies. CONCLUSION (1) EH elicits LTF of GG in normal non-flow limited humans during NREM sleep, without concomitant ventilatory or mechanical LTF. (2) GG activity during the recovery period correlates with the magnitude of GG activation during hypoxia, and inversely with age.

Effect of episodic hypoxia on the susceptibility to hypocapnic central apnea during NREM sleep

We hypothesized that episodic hypoxia (EH) leads to alterations in chemoreflex characteristics that might promote the development of central apnea in sleeping humans. We used nasal noninvasive positive pressure mechanical ventilation to induce hypocapnic central apnea in 11 healthy participants during stable nonrapid eye movement sleep before and after an exposure to EH, which consisted of fifteen 1-min episodes of isocapnic hypoxia (mean O(2) saturation/episode: 87.0 +/- 0.5%). The apneic threshold (AT) was defined as the absolute measured end-tidal PCO(2) (Pet(CO(2))) demarcating the central apnea. The difference between the AT and baseline Pet(CO(2)) measured immediately before the onset of mechanical ventilation was defined as the CO(2) reserve. The change in minute ventilation (V(I)) for a change in Pet(CO(2)) (DeltaV(I)/ DeltaPet(CO(2))) was defined as the hypocapnic ventilatory response. We studied the eupneic Pet(CO(2)), AT Pet(CO(2)), CO(2) reserve, and hypocapnic ventilatory response before and after the exposure to EH. We also measured the hypoxic ventilatory response, defined as the change in V(I) for a corresponding change in arterial O(2) saturation (DeltaV(I)/DeltaSa(O(2))) during the EH trials. V(I) increased from 6.2 +/- 0.4 l/min during the pre-EH control to 7.9 +/- 0.5 l/min during EH and remained elevated at 6.7 +/- 0.4 l/min the during post-EH recovery period (P < 0.05), indicative of long-term facilitation. The AT was unchanged after EH, but the CO(2) reserve declined significantly from -3.1 +/- 0.5 mmHg pre-EH to -2.3 +/- 0.4 mmHg post-EH (P < 0.001). In the post-EH recovery period, DeltaV(I)/DeltaPet(CO(2)) was higher compared with the baseline (3.3 +/- 0.6 vs. 1.8 +/- 0.3 l x min(-1) x mmHg(-1), P < 0.001), indicative of an increased hypocapnic ventilatory response. However, there was no significant change in the hypoxic ventilatory response (DeltaV(I)/DeltaSa(O(2))) during the EH period itself. In conclusion, despite the presence of ventilatory long-term facilitation, the increase in the hypocapnic ventilatory response after the exposure to EH induced a significant decrease in the CO(2) reserve. This form of respiratory plasticity may destabilize breathing and promote central apneas.

Tetraplegia is a risk factor for central sleep apnea

Sleep-disordered breathing (SDB) is highly prevalent in patients with spinal cord injury (SCI); the exact mechanism(s) or the predictors of disease are unknown. We hypothesized that patients with cervical SCI (C-SCI) are more susceptible to central apnea than patients with thoracic SCI (T-SCI) or able-bodied controls. Sixteen patients with chronic SCI, level T6 or above (8 C-SCI, 8 T-SCI; age 42.5 ± 15.5 years; body mass index 25.9 ± 4.9 kg/m(2)) and 16 matched controls were studied. The hypocapnic apneic threshold and CO2 reserve were determined using noninvasive ventilation. For participants with spontaneous central apnea, CO2 was administered until central apnea was abolished, and CO2 reserve was measured as the difference in end-tidal CO2 (PetCO2) before and after. Steady-state plant gain (PG) was calculated from PetCO2 and VE ratio during stable sleep. Controller gain (CG) was defined as the ratio of change in VE between control and hypopnea or apnea to the ΔPetCO2. Central SDB was more common in C-SCI than T-SCI (63% vs. 13%, respectively; P < 0.05). Mean CO2 reserve for all participants was narrower in C-SCI than in T-SCI or control group (-0.4 ± 2.9 vs.-2.9 ± 3.3 vs. -3.0 ± 1.2 l·min(-1)·mmHg(-1), respectively; P < 0.05). PG was higher in C-SCI than in T-SCI or control groups (10.5 ± 2.4 vs. 5.9 ± 2.4 vs. 6.3 ± 1.6 mmHg·l(-1)·min(-1), respectively; P < 0.05) and CG was not significantly different. The CO2 reserve was an independent predictor of apnea-hypopnea index. In conclusion, C-SCI had higher rates of central SDB, indicating that tetraplegia is a risk factor for central sleep apnea. Sleep-related hypoventilation may play a significant role in the mechanism of SDB in higher SCI levels.

Updated Adaptive Servo-Ventilation Recommendations for the 2012 AASM Guideline: "The Treatment of Central Sleep Apnea Syndromes in Adults: Practice Parameters with an Evidence-Based Literature Review and Meta-Analyses".

ABSTRACT An update of the 2012 systematic review and meta-analyses were performed and a modified-GRADE approach was used to update the recommendation for the use of adaptive servo-ventilation (ASV) for the treatment of central sleep apnea syndrome (CSAS) related to congestive heart failure (CHF). Meta-analyses demonstrated an improvement in LVEF and a normalization of AHI in all patients. Analyses also demonstrated an increased risk of cardiac mortality in patients with an LVEF of ≤ 45% and moderate or severe CSA predominant sleep-disordered breathing. These data support a Standard level recommendation against the use of ASV to treat CHF-associated CSAS in patients with an LVEF of ≤ 45% and moderate or severe CSAS, and an Option level recommendation for the use of ASV in the treatment CHF-associated CSAS in patients with an LVEF > 45% or mild CHF-related CSAS. The application of these recommendations is limited to the target patient populations; the ultimate judgment regarding propriety of any specific care must be made by the clinician.

Sustained hyperoxia stabilizes breathing in healthy individuals during NREM sleep

The present study was designed to determine whether hyperoxia would lower the hypocapnic apneic threshold (AT) during non-rapid eye movement (NREM) sleep. Nasal noninvasive mechanical ventilation was used to induce hypocapnia and subsequent central apnea in healthy subjects during stable NREM sleep. Mechanical ventilation trials were conducted under normoxic (room air) and hyperoxic conditions (inspired PO(2) > 250 Torr) in a random order. The CO(2) reserve was defined as the minimal change in end-tidal PCO(2) (PET(CO(2))) between eupnea and hypocapnic central apnea. The PET(CO(2)) of the apnea closest to eupnea was designated as the AT. The hypocapnic ventilatory response was calculated as the change in ventilation below eupnea for a given change in PET(CO(2)). In nine participants, compared with room air, exposure to hyperoxia was associated with a significant decrease in eupneic PET(CO(2)) (37.5 ± 0.6 vs. 41.1 ± 0.6 Torr, P = 0.001), widening of the CO(2) reserve (-3.8 ± 0.8 vs. -2.0 ± 0.3 Torr, P = 0.03), and a subsequent decline in AT (33.3 ± 1.2 vs. 39.0 ± 0.7 Torr; P = 001). The hypocapnic ventilatory response was also decreased with hyperoxia. In conclusion, 1) hyperoxia was associated with a decreased AT and an increase in the magnitude of hypocapnia required for the development of central apnea. 2) Thus hyperoxia may mitigate the effects of hypocapnia on ventilatory motor output by lowering the hypocapnic ventilatory response and lowering the resting eupneic PET(CO(2)), thereby decreasing plant gain.

Cardiovascular Complications of Respiratory Diseases

A major burden of morbidity and mortality due to respiratory diseases can be directly related to the cardiovascular (CV) complications of these disorders. Evidence from cross-sectional and longitudinal studies link reduced lung function and cardiovascular diseases. However, the underlying pathogenic mechanisms are unclear. Hypoxia-induced increased sympathetic activity, blood viscosity, or inflammation, among other factors, may mediate the underlying pathogenesis. In addition, sleep-disordered breathing (SDB) has been implicated by association in multiple CV diseases including hypertension, ischemic heart disease, congestive heart failure, arrhythmias, and stroke. However, the exact contribution of SDB, including obstructive and central sleep apneas, to the development of cardiovascular diseases is not fully understood. In this context, the contribution of the new large, prospective, Jackson Heart Study could be significant in that it is designed to answer several of these questions, specifically in the African American population. This review examines the current evidence that links both reduced lung function and SDB to CV diseases.

Testosterone Conversion Blockade Increases Breathing Stability in Healthy Men during NREM Sleep

STUDY OBJECTIVES Gender differences in the prevalence of sleep apnea/hypopnea syndrome may be mediated via male sex hormones. Our objective was to determine the exact pathway for a testosterone-mediated increased propensity for central sleep apnea via blockade of the 5α-reductase pathway of testosterone conversion by finasteride. DESIGN Randomization to oral finasteride vs. sham, single-center study. SETTING Sleep research laboratory. PARTICIPANTS Fourteen healthy young males without sleep apnea. INTERVENTION Hypocapnia was induced via brief nasal noninvasive positive pressure ventilation during stable NREM sleep. Cessation of mechanical ventilation resulted in hypocapnic central apnea or hypopnea. MEASUREMENTS AND RESULTS The apnea threshold (AT) was defined as the end-tidal CO₂(P(ET)CO₂) that demarcated the central apnea closest to the eupneic P(ET)CO₂. The CO₂ reserve was defined as the difference in P(ET)CO₂ between eupnea and AT. The apneic threshold and CO₂ reserve were measured at baseline and repeated after at a minimum of 1 month. Administration of finasteride resulted in decreased serum dihydrotestosterone. In the finasteride group, the eupneic ventilatory parameters were unchanged; however, the AT was decreased (38.9 ± 0.6 mm Hg vs.37.7 ± 0.9 mm Hg, P = 0.02) and the CO₂ reserve was increased (-2.5 ± 0.3 mm Hg vs. -3.8 ± 0.5 mm Hg, P = 0.003) at follow-up, with a significantly lower hypocapnic ventilatory response, thus indicating increased breathing stability during sleep. No significant changes were noted in the sham group on follow-up study. CONCLUSIONS Inhibition of testosterone action via the 5α-reductase pathway may be effective in alleviating breathing instability during sleep, presenting an opportunity for novel therapy for central sleep apnea in selected populations.

Control of Ventilation in Health and Disease

&NA; Control of ventilation occurs at different levels of the respiratory system through a negative feedback system that allows precise regulation of levels of arterial carbon dioxide and oxygen. Mechanisms for ventilatory instability leading to sleep‐disordered breathing include changes in the genesis of respiratory rhythm and chemoresponsiveness to hypoxia and hypercapnia, cerebrovascular reactivity, abnormal chest wall and airway reflexes, and sleep state oscillations. One can potentially stabilize breathing during sleep and treat sleep‐disordered breathing by identifying one or more of these pathophysiological mechanisms. This review describes the current concepts in ventilatory control that pertain to breathing instability during wakefulness and sleep, delineates potential avenues for alternative therapies to stabilize breathing during sleep, and proposes recommendations for future research.

Effect of age on long-term facilitation and chemosensitivity during NREM sleep

The reason for increased sleep-disordered breathing with a predominance of central apneas in the elderly is unknown. We speculate that ventilatory control instability may provide a link between aging and the onset of unstable breathing during sleep. We sought to investigate potential underlying mechanisms in healthy, elderly adults during sleep. We hypothesized that there is 1) a decline in respiratory plasticity or long-term facilitation (LTF) of ventilation and/or 2) increased ventilatory chemosensitivity in older adults during non-, this should be hyphenated, non-rapid rapid eye movement (NREM) sleep. Fourteen elderly adults underwent 15, 1-min episodes of isocapnic hypoxia (EH), nadir O2 saturation: 87.0 ± 0.8%. Measurements were obtained during control, hypoxia, and up to 20 min of recovery following the EH protocol, respectively, for minute ventilation (VI), timing, and inspiratory upper-airway resistances (RUA). The results showed the following. 1) Compared with baseline, there was a significant increase in VI (158 ± 11%, P < 0.05) during EH, but this was not accompanied by augmentation of VI during the successive hypoxia trials nor in VI during the recovery period (94.4 ± 3.5%, P = not significant), indicating an absence of LTF. There was no change in inspiratory RUA during the trials. This is in contrast to our previous findings of respiratory plasticity in young adults during sleep. Sham studies did not show a change in any of the measured parameters. 2) We observed increased chemosensitivity with increased isocapnic hypoxic ventilatory response and hyperoxic suppression of VI in older vs. young adults during NREM sleep. Thus increased chemosensitivity, unconstrained by respiratory plasticity, may explain increased periodic breathing and central apneas in elderly adults during NREM sleep.