The Relationship Between Breathing and Sleep

Title: Inhalation of low (0.5%–1.5%) CO2 as a potential treatment for apnea of prematurity

Authors: Al-Aif S, Alvaro R, Manfreda J, Kwiatkowski K, Cates D, Rigatto H.

Journal: Semin Perinatol. 2001 Apr;25(2):100-6. doi: 10.1053/sper.2001.23199. PMID: 11339662.

Link to PubMed: Inhalation of low (0.5%–1.5%) CO2 as a potential treatment for apnea of prematurity

Abstract: Apnea of prematurity is common and none of the treatments being used are fully effective and free of significant adverse side effects. We hypothesized that low concentrations of CO2 (< or = 1.5%) may reduce apnea without causing discomfort from an increase in ventilation. We studied 10 preterm infants at a gestational age of 32+/-1 wk (mean +/- SEM) and birthweight 1.8+/-0.2 kg. After a control period of 1 hour, concentrations of CO2 were given (0.5%, 1%, and 1.5%) for 1 hour each, followed by a recovery period of 1 hour. Apnea number significantly decreased from 2.0+/-0.3 apneas/min during control to 1.0+/-0.1 apneas/min (0.5% CO2; P < .05), 1.1+/-0.2 (1% CO2; P < .05), and to 0.7+/-0.2 (1.5% CO2; P < .01). The apnea time significantly decreased from 14.2+/-2.5 s/min during control to 5.2+/-0.8 (0.5% CO2; P < .01), 5.8+/-0.7 (1% CO2; P < .01), and to 3.7+/-0.9 (1.5% CO2; P < .01). Minute ventilation significantly increased with CO2 without evidence of respiratory discomfort. TcPCO2 did not change and TcPO2 increased slightly. These findings suggest that inhalation of low concentrations of CO2 in preterm infants with apnea 1) decreases the number and time of apneas, 2) improves oxygenation, 3) increases ventilation, and 4) is effective even in such low concentrations as 0.5%. We speculate that inhalation of CO2 (< 1%) is more effective and safer than methylxanthines for the treatment of apnea of prematurity.

Title: Carbon Dioxide in Sleep Medicine: The Next Frontier for Measurement, Manipulation, and Research

Authors: Thomas RJ.

Journal: J Clin Sleep Med. 2014 May 15;10(5):523-6. doi: 10.5664/jcsm.3702. PMID: 24910554; PMCID: PMC4046364.

Link to full text: Carbon Dioxide in Sleep Medicine: The Next Frontier for Measurement, Manipulation, and Research

Abstract: Carbon dioxide (CO2) is the most important regulator of respiration and blood pH. Papers are published with scant new information every so often that largely focus on clinical descriptions of hypercapnic individuals, often obese. While there is intense basic science interest in CO2 sensitive neurons in the brainstem, including the Phox2b/neurokinin-1 receptor (NK1R)-expressing neurons in the pre-Bötzinger complex (pre-BötzC),1 and exposing the carotid bodies to hypocapnia induces periodic breathing,2,3 the science and industry of sleep-breathing medicine has generally neglected CO2. Much of the information on chronic exposure to elevated but low levels of CO2 comes from submarine research, targeting sustained ambient concentrations in the low single digits.4–8 Acute exposure to high concentrations of CO2 results in extreme dyspnea and death; the gas has anesthetic properties and can induce a reversible isoelectric EEG.9 Demonstrating slowing of EEG rhythms with hypercapnia10 and power loss in classic oscillatory bands11 (besides increased slow wave sleep associated with respiratory failure12) is nonspecific and not informative on pathobiological mechanisms. Increased inhaled CO2 does suppress cerebral metabolic rate of oxygen13 and reduces resting state functional connectivity.14 While sympathetic drive is reliably increased acutely by hypercapnia, acclimatization mechanisms at the cellular and neural circuit levels, which can be remarkably potent enabling life at otherwise lethal CO2 levels, remain to be elucidated. We are not sure if there is a true CO2 sensor equivalent to hypoxia-inducible factors vs. simply pH mediated changes, or if there are profound direct effects of CO2 on inflammatory responses, the metabolome, the transcriptome, or epigenetic regulation. Widespread systemic dysregulation is plausible, and some data is suggestive. Hypercapnia can induce mitochondrial dysfunction through increased levels on microRNA-183, which decreases expression of isocitrate dehydrogenase.15 Hypoxia-hypercapnia cycles are neurotoxic.16 Obesity hypoventilation (vs. obese controls) was reported to show an increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin, and impaired endothelial function.17

Title: Allergic rhinitis-induced nasal congestion: its impact on sleep quality

Authors: Storms W.

Journal: Prim Care Respir J. 2008 Mar;17(1):7-18. doi: 10.3132/pcrj.2008.00001. PMID: 18253678; PMCID: PMC6619860.

Link to full text: Allergic rhinitis-induced nasal congestion: its impact on sleep quality

Abstract: Allergic rhinitis (AR) is an extremely common health problem affecting 20 to 40 million Americans and between 10-25% of the world's population. Patients with AR suffer from both nasal symptoms (congestion, rhinorrhea, itching, and sneezing) and ocular symptoms (itching, redness, and tearing). The negative impact on sleep quality and quantity, and consequently on various aspects of the patient's life, is an under-recognised and under-treated component of AR morbidity. Nasal congestion, which is one of the most bothersome and prevalent symptoms of AR, is thought to be the leading symptom responsible for rhinitis-related sleep problems. In addition to reducing clinical symptoms, pharmacologic therapies for AR that specifically reduce inflammatory cells and mediators - and therefore nasal congestion and other symptoms - should also improve sleep quality and overall quality of life (QOL). Intranasal corticosteroids (INS) are the current mainstay of therapy for AR. Results of a number of clinical trials demonstrate that INS effectively reduce nasal congestion and ocular symptoms, improve sleep quality, and decrease daytime somnolence. Intranasal corticosteroids have also proved to be effective in reducing symptoms of acute rhinosinusitis and nasal polyposis, both of which also negatively impact on sleep quality. Intranasal corticosteroids are considered safe due to their low systemic bioavailability.

Title: Alternative approaches to treatment of Central Sleep Apnea

Authors: Thomas RJ.

Journal: Sleep Med Clin. 2014 Mar 1;9(1):87-104. doi: 10.1016/j.jsmc.2013.10.008. PMID: 24772053; PMCID: PMC3998090.

Link to full text: Alternative approaches to treatment of Central Sleep Apnea

Abstract: Divergent approaches to treatment of hypocapnic central sleep apnea syndromes reflect the difficulties in taming a hyperactive respiratory chemoreflex. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable non-rapid eye movement (NREM) sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient dyssynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Provent and Winx may be less likely to trigger central apneas or periodic breathing in those with a narrow CO2 reserve. An oral appliance can meaningfully reduce positive pressure requirements and thus enable treatment of complex apnea. Novel pharmacological approaches may target mediators of carotid body glomus cell excitation, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is not always successful, and multi-modality therapy might need to be considered. Phenotyping of sleep apnea beyond conventional scoring approaches is the key to optimal management.

Keywords: Winx; acetazolamide Provent; carbon dioxide; central apnea; multimodal complex; oxygen rebreathing; periodic breathing.

Title: Better quality of life when nasal breathing of snoring men is improved at night

Authors: Löth S, Petruson B, Wirén L, Wilhelmsen L.

Journal: Arch Otolaryngol Head Neck Surg. 1999 Jan;125(1):64-7. doi: 10.1001/archotol.125.1.64. PMID: 9932590.

Link to PubMed: Better quality of life when nasal breathing of snoring men is improved at night

Abstract: Objective: To evaluate whether improved nasal breathing changes the quality of life in snoring men and improves the female sleeping partners' well-being in the morning.

Design: During 1 month, 42 heavily snoring men slept with a nostril dilator. Before and after 1 month, the snorers rated their daytime tiredness and completed the Nottingham Health Profile questionnaire. Female sleeping partners rated the snoring, the quality of their sleep, and their sense of well-being in the morning. A population sample was used for comparison.

Setting: The Central Hospital, Skövde, Sweden.

Results: The snorers' quality of life before the study was significantly worse (P<.001) than that of the comparison population and improved significantly (P = .001). The men were significantly (P<.001) less tired during the day when their nasal airflow was increased. Female sleeping partners had significantly (P = .005) better sleep and an improved sense of well-being in the morning during the test period. Both were correlated with a significant reduction in the snoring (P<.001).

Conclusions: When nasal breathing of snoring men was improved at night, their quality of life was significantly improved. The female sleeping partners had a reduction in sleep disturbance that correlated well with an improvement in their own sleep and feelings of well-being in the morning.

Title: Blowing past the apneic threshold

Authors: Johal A, Lenet A, Sigua NL.

Journal: J Clin Sleep Med. 2022 Oct 1;18(10):2515-2518. doi: 10.5664/jcsm.10162. PMID: 35859324; PMCID: PMC9516585.

Link to full text: Blowing past the apneic threshold

Abstract: An 81-year-old man with severe obstructive sleep apnea, hypertension, and obesity (body mass index 32 kg/m2) presented to the sleep clinic for an initial evaluation. He has been on auto-titrating bilevel positive airway pressure (BPAP) with 2 L/min nocturnal oxygen for more than 10 years and has been adherent to therapy. He has no known cardiopulmonary disorder and was not on opiates, benzodiazepines, or other respiratory depressants. He denied tobacco, drug, or alcohol use. His initial sleep study, the indication for nocturnal oxygen supplementation, and serum bicarbonate level were not available for review.

Title: Central sleep apnea: pathophysiologic classification

Authors: Javaheri S, Badr MS.

Journal: Sleep. 2023 Mar 9;46(3):zsac113. doi: 10.1093/sleep/zsac113. PMID: 35551411; PMCID: PMC9995798.

Link to full text: Central sleep apnea: pathophysiologic classification

Abstract: Central sleep apnea is not a single disorder; it can present as an isolated disorder or as a part of other clinical syndromes. In some conditions, such as heart failure, central apneic events are due to transient inhibition of ventilatory motor output during sleep, owing to the overlapping influences of sleep and hypocapnia. Specifically, the sleep state is associated with removal of wakefulness drive to breathe; thus, rendering ventilatory motor output dependent on the metabolic ventilatory control system, principally PaCO2. Accordingly, central apnea occurs when PaCO2 is reduced below the "apneic threshold". Our understanding of the pathophysiology of central sleep apnea has evolved appreciably over the past decade; accordingly, in disorders such as heart failure, central apnea is viewed as a form of breathing instability, manifesting as recurrent cycles of apnea/hypopnea, alternating with hyperpnea. In other words, ventilatory control operates as a negative-feedback closed-loop system to maintain homeostasis of blood gas tensions within a relatively narrow physiologic range, principally PaCO2. Therefore, many authors have adopted the engineering concept of "loop gain" (LG) as a measure of ventilatory instability and susceptibility to central apnea. Increased LG promotes breathing instabilities in a number of medical disorders. In some other conditions, such as with use of opioids, central apnea occurs due to inhibition of rhythm generation within the brainstem. This review will address the pathogenesis, pathophysiologic classification, and the multitude of clinical conditions that are associated with central apnea, and highlight areas of uncertainty.

Keywords: Adaptive-Servo Ventilation (ASV); apneic threshold; bi-level positive pressure therapy (BPAP); central apnea; continuous positive pressure therapy (CPAP); controller gain; hypocapnia; loop gain; plant gain.

Title: CO2 homeostasis during periodic breathing in obstructive sleep apnea

Authors: Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM.

Journal: J Appl Physiol (1985). 2000 Jan;88(1):257-64. doi: 10.1152/jappl.2000.88.1.257. PMID: 10642388.

Link to full text: CO2 homeostasis during periodic breathing in obstructive sleep apnea

Abstract: The contribution of apnea to chronic hypercapnia in obstructive sleep apnea (OSA) has not been clarified. Using a model (D. M. Rapoport, R. G. Norman, and R. M. Goldring. J. Appl. Physiol. 75: 2302-2309, 1993), we previously illustrated failure of CO2 homeostasis during periodic breathing resulting from temporal dissociation between ventilation and perfusion ("temporal V/Q mismatch"). This study measures acute kinetics of CO2 during periodic breathing and addresses interapnea ventilatory compensation for maintenance of CO2 homeostasis in 11 patients with OSA during daytime sleep (37-171 min). Ventilation and expiratory CO2 and O2 fractions were measured on a breath-by-breath basis by means of a tight-fitting full facemask. Calculations included CO2 excretion, metabolic CO2 production, and CO2 balance (metabolic CO2 production - exhaled CO2). CO2 balance was tabulated for each apnea/hypopnea event-interevent cycle and as a cumulative value during sleep. Cumulative CO2 balance varied (-3,570 to +1,388 ml). Positive cumulative CO2 balance occurred in the absence of overall hypoventilation during sleep. For each cycle, positive CO2 balance occurred despite increased interevent ventilation to rates as high as 45 l/min. This failure of CO2 homeostasis was dependent on the event-to-interevent duration ratio. The results demonstrate that 1) periodic breathing provides a mechanism for acute hypercapnia in OSA, 2) acute hypercapnia during periodic breathing may occur without a decrease in average minute ventilation, supporting the presence of temporal V/Q mismatch, as predicted from our model, and 3) compensation for CO2 accumulation during apnea/hypopnea may be limited by the duration of the interevent interval. The relationship of this acute hypercapnia to sustained chronic hypercapnia in OSA remains to be further explored.

Title: Effect of Breathe Right nasal strip on snoring

Authors: Ulfberg J, Fenton G.

Journal: Rhinology. 1997 Jun;35(2):50-2. PMID: 9299650.

Link to PubMed: Effect of Breathe Right nasal strip on snoring

Abstract: Snoring is a significant problem both for the patient and for the bedpartner. It is well known that nasal stuffiness can contribute to snoring, and sleep quality may deteriorate because of the snoring. Nasal dilation can reduce snoring and improve sleep. Thirty-five habitual snorers (18 female, 17 male) and their bedpartners participated in an open label study. The patients were diagnosed as heavy snorers after they underwent overnight polysomnography showing that their apnoea indexes were below 5, thus sleep apnoea patients were not included in the study. The participants and their partners filled out evaluations concerning snoring intensity, mouth dryness and Epworth Sleepiness Scale prior to and after using Breath Right nasal strips for 14 consecutive nights. The Breathe Right external nasal dilator is a simple, nonpharmaceutical method to decrease nasal airway resistance and thus potentially reduce or eliminate snoring. After using the strips there were statistically significant decreases in snoring (p < 0.001) as graded by the bed partner, and in mouth dryness (p = 0.025) and in the Epworth Sleepiness Scale scores (p = 0.001), as graded by the patient. The results of this study indicate that Breathe Right nasal strips may be used to reduce snoring, mouth dryness and sleepiness in patients presenting with symptoms of snoring.

Title: Effect of hypoxia on the hypopnoeic and apnoeic threshold for CO(2) in sleeping humans

Authors: Xie A, Skatrud JB, Dempsey JA.

Journal: J Physiol. 2001 Aug 15;535(Pt 1):269-78. doi: 10.1111/j.1469-7793.2001.00269.x. PMID: 11507176; PMCID: PMC2278764.

Link to full text: Effect of hypoxia on the hypopnoeic and apnoeic threshold for CO(2) in sleeping humans

Abstract: 1. Rhythmic breathing during sleep requires that P(CO2) be maintained above a sensitive hypocapnic apnoeic threshold. Hypoxia causes periodic breathing during sleep that can be prevented or eliminated with supplemental CO(2). The purpose of this study was to determine the effect of hypoxia in changing the difference between the eupnoeic P(CO2) and the P(CO2) required to produce hypopnoea or apnoea (hypopnoea/apnoeic threshold) in sleeping humans. 2. The effect of hypoxia on eupnoeic end-tidal partial pressure of CO(2) (P(ET,CO2)) and hypopnoea/apnoeic threshold P(ET,CO2) was examined in seven healthy, sleeping human subjects. A bilevel pressure support ventilator in a spontaneous mode was used to reduce P(ET,CO2) in small decrements by increasing the inspiratory pressure level by 2 cmH2O every 2 min until hypopnoea (failure to trigger the ventilator) or apnoea (no breathing effort) occurred. Multiple trials were performed during both normoxia and hypoxia (arterial O(2) saturation, S(a,O2) = 80 %) in a random order. The hypopnoea/apnoeic threshold was determined by averaging P(ET,CO2) of the last three breaths prior to each hypopnoea or apnoea. 3. Hypopnoeas and apnoeas were induced in all subjects during both normoxia and hypoxia. Hypoxia reduced the eupnoeic P(ET,CO2) compared to normoxia (42.4 +/- 1.3 vs. 45.0 +/- 1.1 mmHg, P < 0.001). However, no change was observed in either the hypopnoeic threshold P(ET,CO2) (42.1 +/- 1.4 vs. 43.0 +/- 1.2 mmHg, P > 0.05) or the apnoeic threshold P(ET,CO2) (41.3 +/- 1.2 vs. 41.6 +/- 1.0 mmHg, P > 0.05). Thus, the difference in P(ET,CO2) between the eupnoeic and threshold levels was much smaller during hypoxia than during normoxia (-0.2 +/- 0.2 vs. -2.0 +/- 0.3 mmHg, P < 0.01 for the hypopnoea threshold and -1.1 +/- 0.2 vs. -3.4 +/- 0.3 mmHg, P < 0.01 for the apnoeic threshold). We concluded that hypoxia causes a narrowing of the difference between the baseline P(ET,CO2) and the hypopnoea/apnoeic threshold P(ET,CO2), which could increase the likelihood of ventilatory instability.

Title: Effect of nasal dilation on snoring and apneas during different stages of sleep

Authors: Hoffstein V, Mateika S, Metes A.

Journal: Sleep. 1993 Jun;16(4):360-5. doi: 10.1093/sleep/16.4.360. PMID: 8141871

Link to PubMed: Effect of nasal dilation on snoring and apneas during different stages of sleep

Abstract: This study was designed to test the hypothesis that nasal dilation reduces snoring. To achieve this we performed nocturnal polysomnography, including measurement of snoring, in 15 patients without nasal pathology before and after insertion of a nasal dilator (NOZOVENT). Snoring was quantified for each sleep stage by recording the number of snores per minute of sleep, number of snores per minute of snoring time and nocturnal sound intensities (maximum, average and minimum). We found that nasal dilation had no effect on the number of apneas, hypopneas or oxygen saturation. Snoring parameters were unaffected by NOZOVENT during stages I, II and REM sleep, but were all significantly reduced during slow wave sleep. We conclude that dilation of the anterior nares in patients without nasal pathology has a relatively weak effect on snoring, and routine use of nasal dilating appliances is not recommended for treatment of snoring.

Title: Hypocapnia is associated with increased upper airway expiratory resistance during sleep

Authors: Sankri-Tarbichi AG, Richardson NN, Chowdhuri S, Rowley JA, Safwan Badr M.

Journal: Respir Physiol Neurobiol. 2011 Jul 31;177(2):108-13. doi: 10.1016/j.resp.2011.04.004. Epub 2011 Apr 13. PMID: 21513820; PMCID: PMC3113471.

Link to full text: Hypocapnia is associated with increased upper airway expiratory resistance during sleep

Abstract: We hypothesized that hypocapnia is responsible for increased expiratory resistance during NREM sleep. Hypocapnia was induced by hypoxic hyperventilation in 21 subjects (aged 29.4 ± 7.8 yrs, 10 women, BMI 24.4 ± 4.3 kg/m(2)). Isocapnic hypoxia was induced in 12 subjects of whom, 6 underwent hypocapnic hypoxia in the same night. Upper airway resistance (R(UA)) was measured at the linear pressure-flow relationship during inspiration and expiration. Inspiratory flow limitation (IFL) was defined as the dissociation in pressure-flow relationship. (1) Expiratory R(UA) increased during hypocapnic but not isocapnic hypoxia relative to control (11.0 ± 5.6 vs. 8.2 ± 3.6 cm H(2)O/L/s; p < 0.05, and 11.45.0 vs. 10.94.4 cm H(2)O/L/s; p = NS, respectively). (2) No gender difference was found in R(UA) (p = NS). (3) Increased expiratory R(UA) correlated with the IFL change during hypocapnic but not isocapnic hypoxia. (4) No changes were noted in inspiratory R(UA) or IFL. Expiratory R(UA) increased during hypocapnia and was associated with IFL, indicating upper airway narrowing. Gender does not influence the upper airway response to hypocapnic hypoxia.

Title: Improved nasal breathing reduces snoring and morning tiredness. A 6-month follow-up study

Authors: Löth S, Petruson B.

Journal: Arch Otolaryngol Head Neck Surg. 1996 Dec;122(12):1337-40. doi: 10.1001/archotol.1996.01890240045010. PMID: 8956746.

Link to PubMed: Improved nasal breathing reduces snoring and morning tiredness. A 6-month follow-up study

Abstract: Background: Dilation of the nasal valve region can increase the ability to breathe through the nose and reduce the negative intrathoracic pressure required for inspiration. Vibrations of the palate and soft tissues of the throat, which generate snoring sounds, can be prevented when patients inhale less heavily.

Objectives: To evaluate the effect a nostril dilator has on patient snoring and tiredness in the morning and to determine how many patients would continue to use the device for half a year.

Design: For 6 months, 42 men who were heavy snorers graded their average tiredness in the morning and the patient's sleeping partner graded the average snoring using a visual analog scale from 0 to 100.

Setting: All patients were examined at the Department of Otorhinolaryngology, Central Hospital, in Skövde, Sweden.

Results: When the nostril dilator was used there was a significant decrease in snoring after both 1- and 6-month reports. There was a significant correlation between diminution of snoring and less tiredness in patients in the morning. The compliance was good since 60% of patients continued to use the device during the 6-month test period.

Conclusions: This study illustrates the benefits that reducing nasal airway resistance during sleep has on snoring and morning tiredness in patients.

Title: Influence of longterm CPAP therapy on CO2 drive in patients with obstructive sleep apnea

Authors: Verbraecken J, Willemen M, De Cock W, Wittesaele W, Govaert K, Van de Heyning P, De Backer W.

Journal: Respir Physiol. 2000 Oct;123(1-2):121-30. doi: 10.1016/s0034-5687(00)00140-7. PMID: 10996193.

Link to PubMed: Influence of longterm CPAP therapy on CO2 drive in patients with obstructive sleep apnea

Abstract: According to recent publications, the values of the hypercapnic ventilatory responses (HCVR) in normocapnic obstructive sleep apnea (OSA) patients are highly variable, but they are usually within the normal range. In our study, CPAP therapy during 1 month did not seem to influence the HCVR [Verbraecken, J., De Backer, W., Willemen, M., De Cock, W., Wittesaele, W., Van de Heyning, P., 1995. Respir. Physiol. 101, 279-287]. It is, however, not well studied whether long term (1 year) CPAP therapy can influence HCVR in normocapnic patients. Therefore, we evaluated the effect of 1 year CPAP therapy on CO(2) drive in 20 OSA patients. The slope of HCVR (SHCVR) changed from 2.35+/-0.21 L min(-1) mmHg(-1) (control) to 1.66+/-0.16 L min(-1) mm Hg(-1) (P=0.04), but the mean within subject coefficient of variation in repeated measurements of SHCVR in treated and untreated OSA patients was not statistically different. Pa(O(2)) increased from 72+/-2 mm Hg to 80+/-2 (1 year) mm Hg. We conclude that CPAP therapy improves daytime gas exchange in normocapnic OSA and may possibly decrease CO(2) drive (slope) after a treatment period of 1 year.

Title: Low-concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing

Authors: Thomas RJ, Daly RW, Weiss JW.

Journal: Sleep. 2005 Jan;28(1):69-77. doi: 10.1093/sleep/28.1.69. PMID: 15700722.

Link to PubMed: Low-concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing

Abstract: Objectives: To assess the efficacy of added carbon dioxide as adjunctive therapy to positive airway pressure-refractory mixed obstructive and central sleep-disordered breathing, using a prototype device-the positive airway pressure gas modulator.

Design: Open-label evaluation of low concentrations of carbon dioxide added to a positive airway pressure circuit.

Setting: Physician-attended polysomnographic titration in a free-standing sleep laboratory with end-tidal and transcutaneous carbon-dioxide monitoring.

Patients: Six adult men (age 54 +/- 5.7 years) with severe poorly controlled mixed sleep-disordered breathing in the absence of renal or heart failure.

Interventions: Flow-independent addition of incremental concentrations of carbon dioxide during sleep.

Measurements and results: The respiratory disturbance index before treatment was 66 +/- 14.5 events per hour of sleep, with a nocturnal desaturation low of 84.6% +/- 10.1%. Residual respiratory disturbance index on best treatment was 43 +/- 9 events per hour of sleep. There was an immediate (<1 minute) response to the addition of 0.5% to 1% carbon dioxide, and minimal changes were required to be made across the night. There was no discomfort, shortness of breath, palpitations, headache, or significant increase in respiratory or heart rate. The residual respiratory disturbance index on carbon dioxide, scored irrespective of desaturations, was in the normal range (< 5 / hour of sleep). Two subjects had a second night at the concentration of carbon dioxide determined to be efficacious, with no required concentration change. No adverse effects on overall sleep architecture were noted.

Conclusions: Low concentrations of carbon dioxide added to conventional positive airway pressure effectively control severe treatment-resistant mixed obstructive and central sleep-disordered breathing.

Title: Objective assessment of nasal obstruction in snoring and obstructive sleep apnea patients: experience of a Police Authority Hospital

Authors: Kalam I.

Journal: Ann Saudi Med. 2002 May-Jul;22(3-4):158-62. doi: 10.5144/0256-4947.2002.158. PMID: 17159386.

Link to full text: Objective assessment of nasal obstruction in snoring and obstructive sleep apnea patients: experience of a Police Authority Hospital

Abstract: Background: The role of nasal airflow resistance in the pathogenesis of obstructive sleep apnea (OSA) syndrome remains contentious. The aim of this study was to investigate the changes in apnea index in response to nasal surgery, as guided by acoustic rhinometry.

Patients and methods: Forty-five patients were referred for complaints of snoring and nasal obstruction. The patients were divided into two groups according to the severity of nasal obstruction: group 1 (nasal obstruction was the predominant symptom) included 21 patients, and group 2 (snoring was the predominant symptom) included 24 patients. In group 1, nasal surgery was performed as a first surgical procedure and was followed after 10-12 weeks by palatal surgery. In group 2, palatal surgery was performed as the primary procedure and was followed after 10-12 weeks by nasal surgery.

Results: The results showed a clear relationship between the correction of nasal obstruction and the severity of OSA, as indicated by measuring the apnea index (AI). However, in none of the group 1 cases was nasal surgery alone capable of reducing the AI by 50%. In group 2, palatal surgery effectively reduced AI, and when followed by nasal surgery, the reduction in AI was again statistically significant.

Conclusion: This indicates that nasal obstruction could be considered a contributing factor to the severity of OSA, but not a causative factor in the production of OSA. It also indicates that nasal surgery and palatal surgery combined are effective in improving snoring and OSA in properly selected patients.

Title: A review of preventing central sleep apnea by inspired CO2

Authors: Mulchrone A, Shokoueinejad M, Webster J.

Journal: Physiol Meas. 2016 May;37(5):R36-45. doi: 10.1088/0967-3334/37/5/R36. Epub 2016 Apr 19. PMID: 27093535.

Link to PubMed: A review of preventing central sleep apnea by inspired CO2

Abstract: Although almost completely unknown half a century ago, sleep disorders are gaining recognition as major issues to public health due to their growing prevalence and dire societal consequences. Despite being linked to several infamous catastrophic events such as Chernobyl, it is estimated that 90% of sufferers fail to get diagnosed and receive treatment, and a significant portion of the ones that do are often non-compliant due to the side effects of current treatments. This article presents a review of the current standard treatment for central sleep apnea, and investigates the advantages and possible consequences of using inspired carbon dioxide (CO2) as an alternative treatment option.

Title: Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea

Authors: Xie A, Rankin F, Rutherford R, Bradley TD.

Journal: J Appl Physiol (1985). 1997 Mar;82(3):918-26. doi: 10.1152/jappl.1997.82.3.918. PMID: 9074983.

Link to full text: Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea

Abstract: We hypothesized that reductions in arterial PCO2 (PaCO2) below the apnea threshold play a key role in the pathogenesis of idiopathic central sleep apnea syndrome (ICSAS). If so, we reasoned that raising PaCO2 would abolish apneas in these patients. Accordingly, patients with ICSAS were studied overnight on four occasions during which the fraction of end-tidal CO2 and transcutaneous PCO2 were measured: during room air breathing (N1), alternating room air and CO2 breathing (N2), CO2 breathing all night (N3), and addition of dead space via a face mask all night (N4). Central apneas were invariably preceded by reductions in fraction of end-tidal CO2. Both administration of a CO2-enriched gas mixture and addition of dead space induced 1- to 3-Torr increases in transcutaneous PCO2, which virtually eliminated apneas and hypopneas; they decreased from 43.7 +/- 7.3 apneas and hypopneas/h on N1 to 5.8 +/- 0.9 apneas and hypopneas/h during N3 (P < 0.005), from 43.8 +/- 6.9 apneas and hypopneas/h during room air breathing to 5.9 +/- 2.5 apneas and hypopneas/h of sleep during CO2 inhalation during N2 (P < 0.01), and to 11.6% of the room air level while the patients were breathing through added dead space during N4 (P < 0.005). Because raising PaCO2 through two different means virtually eliminated central sleep apneas, we conclude that central apneas during sleep in ICSA are due to reductions in PaCO2 below the apnea threshold.

Title: Effect of CO2 inhalation on central sleep apnea and arousals from sleep

Authors: Szollosi I, Jones M, Morrell MJ, Helfet K, Coats AJ, Simonds AK.

Journal: Respiration. 2004 Sep-Oct;71(5):493-8. doi: 10.1159/000080634. PMID: 15467327.

Link to PubMed: Effect of CO2 inhalation on central sleep apnea and arousals from sleep

Abstract: Background: CO(2) inhalation reduces central sleep apnea (CSA) in patients with congestive heart failure (CHF) and idiopathic CSA. CO(2) is also a stimulus for cortical arousal, which has been linked to increased sympathetic nerve activity (SNA) and increased mortality in CHF patients with CSA.

Objective: We have tested the hypothesis that during sleep, inhalation of CO(2) sufficient to reduce the apnea-hypopnea index (AHI) would not reduce the arousal index (AroI).

Methods: In 10 male patients with CSA (7 with CHF and 3 with idiopathic CSA), the inspired CO(2) concentration was increased to raise the sleeping end-tidal CO(2) by 2-4 mm Hg during established stage 2 sleep. Each intervention was maintained for a 10-min period. Sleep stage was monitored with electroencephalograms, electrooculograms, submental electromyogram, airflow with pneumotachometer and respiratory effort and blood gases with oxygen saturation and end-tidal CO(2). During periods of air and CO(2) breathing, AHI and AroI were compared with paired t tests; patients acted as their own controls.

Results: Inhalation of CO(2) produced a significant reduction in AHI (mean +/- SEM) from 74.4 +/- 12.4 events/h during air breathing to 25.8 +/- 7.8 events/h with CO(2) inhalation (p = 0.002). However, the AroI was not significantly different between the two conditions, air 67.8 +/- 12.3 events/h and CO(2) inhalation 52.8 +/- 12.4 events/h (p = 0.264).

Conclusion: CO(2) inhalation reverses CSA but not arousals from sleep. Our findings highlight the need for treatment options that reduce both respiratory events and decrease arousals from sleep, with their associated SNA sequelae.

Title: Carbon dioxide in sleep medicine: the next frontier for measurement, manipulation, and research

Authors: Thomas RJ.

Journal: J Clin Sleep Med. 2014 May 15;10(5):523-6. doi: 10.5664/jcsm.3702. PMID: 24910554; PMCID: PMC4046364.

Link to full text: Carbon dioxide in sleep medicine: the next frontier for measurement, manipulation, and research

Abstract: Carbon dioxide (CO2) is the most important regulator of respiration and blood pH. Papers are published with scant new information every so often that largely focus on clinical descriptions of hypercapnic individuals, often obese. While there is intense basic science interest in CO2 sensitive neurons in the brainstem, including the Phox2b/neurokinin-1 receptor (NK1R)-expressing neurons in the pre-Bötzinger complex (pre-BötzC),1 and exposing the carotid bodies to hypocapnia induces periodic breathing,2,3 the science and industry of sleep-breathing medicine has generally neglected CO2.

Title: Obstructive sleep apnoea and breathing retraining

Authors: Birch M.

Journal: Aust Nurs J. 2004 Aug;12(2):27-9. PMID: 19160562.

Link to PubMed: Obstructive sleep apnoea and breathing retraining

Abstract: Obstructive sleep apnoea (OSA) is a sleep disorder where repeated upper airway obstruction during sleep leads to a decrease in blood oxygen saturation and disrupted sleep. Current treatment options include oral appliances, surgery, and/or the use of a continuous positive airway pressure (CPAP) machine. However, breathing retraining with the Buteyko Institute Method (BIM) is a safe, effective and convenient approach to OSA that could help eliminate the need for surgery or CPAP. This paper examines the role of breathing retraining in OSA and presents a case study to illustrate its effectiveness.

Title: Pathogenesis of upper airway occlusion during sleep

Authors: Remmers JE, deGroot WJ, Sauerland EK, Anch AM.

Journal: J Appl Physiol Respir Environ Exerc Physiol. 1978 Jun;44(6):931-8. doi: 10.1152/jappl.1978.44.6.931. PMID: 670014.

Link to full text: Pathogenesis of upper airway occlusion during sleep

Abstract: Ten patients with daytime somnolence and obesity were found to have periodic airway occlusion (AO) during nocturnal sleep. The cyclical ventilatory pattern consisted of a series of regular inspiratory efforts against an occluded airway (occlusive phase) alternating with a period of regular breathing (ventilatory phase). Significant periods of central respiratory apnea were observed only in one case. The effects of pharyngeal intubation and pharyngeal pressure recordings showed that the locus of airway closure lay in the oropharynx. The genioglossal electromyogram (EMG) consistently revealed periodicity: low level activity at the onset of occlusion and prominent discharge at the instant of pharyngeal opening. In one case, this activity was closely related to pharyngeal patency, whereas in other cases there was considerable overlap between EMG values recorded during occluded and ventilatory phases. In these cases, the relationship of genioglossal discharge to pharyngeal pressure correlated with the presence or absence of pharyngeal occlusion. We speculate that genioglossal force acts to open the oropharynx and that negative pharyngeal pressure promotes pharyngeal closure. The results are consistent with the idea that, once the pharvnx has collapsed, relative recruitment of genioglossal and inspiratory muscle act.ivity is such that the latter influence outstrips the former, so that pharyngeal transmural pressure increases more than genioglossal force. Pharyngeal opening occurs coincident with arousal and preferential activation of the genioglossus muscle of the tongue.

Title: Rethinking O2, CO2 and breathing during wakefulness and sleep

Authors: Dempsey JA, Gibbons TD.

Journal: J Physiol. 2024 Nov;602(21):5571-5585. doi: 10.1113/JP284551. Epub 2023 Sep 26. PMID: 37750243.

Link to PubMed: Rethinking O2, CO2 and breathing during wakefulness and sleep

Abstract: We have examined the importance of three long-standing questions concerning chemoreceptor influences on cardiorespiratory function which are currently experiencing a resurgence of study among physiologists and clinical investigators. Firstly, while carotid chemoreceptors (CB) are required for hypoxic stimulation of breathing, use of an isolated, extracorporeally perfused CB preparation in unanaesthetized animals with maintained tonic input from the CB, reveals that extra-CB hypoxaemia also provides dose-dependent ventilatory stimulation sufficient to account for 40-50% of the total ventilatory response to steady-state hypoxaemia. Extra-CB hyperoxia also provides a dose- and time-dependent hyperventilation. Extra-CB sites of O2-driven ventilatory stimulation identified to date include the medulla, kidney and spinal cord. Secondly, using the isolated or denervated CB preparation in awake animals and humans has demonstrated a hyperadditive effect of CB sensory input on central CO2 sensitivity, so that tonic CB activity accounts for as much as 35-40% of the normal, air-breathing eupnoeic drive to breathe. Thirdly, we argue for a key role for CO2 chemoreception and the neural drive to breathe in the pathogenesis of upper airway obstruction during sleep (OSA), based on the following evidence: (1) removal of the wakefulness drive to breathe enhances the effects of transient CO2 changes on breathing instability; (2) oscillations in respiratory motor output precipitate pharyngeal obstruction in sleeping subjects with compliant, collapsible airways; and (3) in the majority of patients in a large OSA cohort, a reduced neural drive to breathe accompanied reductions in both airflow and pharyngeal airway muscle dilator activity, precipitating airway obstruction.

Keywords: extra‐carotid chemoreceptor O2 sensing; obstructive sleep apnoea; peripheral‐central chemoreceptor interdependence.