The Science of Respiration and Breathing

Title: Humans without a sense of smell breathe differently

Authors: Gorodisky, L., Honigstein, D., Weissbrod, A. et al.

Journal: Nat Commun 15, 8809 (2024). https://doi.org/10.1038/s41467-024-52650-6

Link to full text: Humans without a sense of smell breathe differently

Abstract: Olfaction may play a restricted role in human behavior, yet paradoxically, its absence in anosmia is associated with diverse deleterious outcomes, culminating in reduced life expectancy. The mammalian nose serves two purposes: olfaction and breathing. Because respiratory patterns are impacted by odors, we hypothesized that nasal respiratory airflow may be altered in anosmia. We apply a wearable device that precisely logs nasal airflow for 24-hour-long sessions in participants with isolated congenital anosmia and controls. We observe significantly altered patterns of respiratory nasal airflow in anosmia in wake and in sleep. These differences allow classification of anosmia at 83% accuracy using the respiratory trace alone. Patterns of respiratory airflow have pronounced impact on health, emotion and cognition. We therefore suggest that a portion of the deleterious outcomes associated with anosmia may be attributed to altered patterns of respiratory nasal airflow rather than a direct result of lost odor perception per se.

Title: Dismantling the Component-Specific Effects of Yogic Breathing: Feasibility of a Fully Remote Three-Arm RCT with Virtual Laboratory Visits and Wearable Physiology

Authors: Ma Y, Yang H, Vazquez M, Buraks O, Haack M, Mullington JM, Goldstein MR.

Journal: Int J Environ Res Public Health. 2023 Feb 11;20(4):3180. doi: 10.3390/ijerph20043180. PMID: 36833875; PMCID: PMC9958552.

Link to full text: Dismantling the Component-Specific Effects of Yogic Breathing: Feasibility of a Fully Remote Three-Arm RCT with Virtual Laboratory Visits and Wearable Physiology

Abstract: Despite the growing research base examining the benefits and physiological mechanisms of slow-paced breathing (SPB), mindfulness (M), and their combination (as yogic breathing, SPB + M), no studies have directly compared these in a ”dismantling” framework. To address this gap, we conducted a fully remote three-armed feasibility study with wearable devices and video-based laboratory visits. Eighteen healthy participants (age 18–30 years, 12 female) were randomized to one of three 8-week interventions: slow-paced breathing (SPB, N = 5), mindfulness (M, N = 6), or yogic breathing (SPB + M, N = 7). The participants began a 24-h heart rate recording with a chest-worn device prior to the first virtual laboratory visit, consisting of a 60-min intervention-specific training with guided practice and experimental stress induction using a Stroop test. The participants were then instructed to repeat their assigned intervention practice daily with a guided audio, while concurrently recording their heart rate data and completing a detailed practice log. The feasibility was determined using the rates of overall study completion (100%), daily practice adherence (73%), and the rate of fully analyzable data from virtual laboratory visits (92%). These results demonstrate feasibility for conducting larger trial studies with a similar fully remote framework, enhancing the ecological validity and sample size that could be possible with such research designs.

Title: Increased net water loss by oral compared to nasal expiration in healthy subjects

Authors: Svensson S, Olin AC, Hellgren J.

Journal: Rhinology. 2006 Mar;44(1):74-7. PMID: 16550955.

Link to full text: Increased net water loss by oral compared to nasal expiration in healthy subjects

Abstract:
Aim of the study: To compare the difference in respiratory water loss during expiration through the nose and through the mouth, in healthy subjects.

Methods: The study included 19 healthy, non-smoking volunteers without any present history of non-infectious rhinitis, presenting with symptoms of rhinitis, asthma or previous nasal surgery. Nasal and oral expiratory breath condensates were collected using a breath condenser during tidal respiration at indoor resting conditions. During the nasal breath condensate sampling, the subjects were breathing into a transparent face mask covering the nose and the mouth with the mouth closed. During the oral breath condensate sampling, the subjects inhaled through the nose and exhaled through a mouthpiece connected to the condenser. The airflow during the sampling was assessed with a dry-spirometer connected to the condenser. Sampling was stopped after 100 litres of expired air for each breathing mode. Nasal sampling was done before and after decongestion of the nasal mucosa with oxymetazoline, 0.5 mg/ml. The effect on the nasal mucosa was assessed with acoustic rhinometry.

Results: The mean loss of expired water was 42% less by nasal expiration before decongestion than by oral expiration (1.9 x 10(-3) g/L min compared to 2.7 x 10(-3) g/L min, p < 0.001). The mean expiratory minute ventilation was 9.0 L/min by nasal respiration and 9.8 L/min by oral respiration. Decongestion of the nasal mucosa showed a mean increase of the cross-sectional area at 4 cm from the nostril (1.44 to 1.67 cm2, p = 0.0024), but there was no effect on the net water loss (1.9 x 10(-3) g/Lmin vs 1.9 x 10(-3) g/Lmin).

Conclusion: This study showed that the net water loss increased by 42% when the breathing mode was switched from nasal to oral expiration during tidal breathing in healthy subjects. Increased water and energy loss by oral breathing could be a contributing factor to the symptoms seen in patients suffering from nasal obstruction.

Title: Levels of end-tidal carbon dioxide are low despite normal respiratory rate in individuals with long COVID

Authors: Wood J, Tabacof L, Tosto-Mancuso J, McCarthy D, Kontorovich A, Putrino D.

Journal: J Breath Res. 2021 Dec 8;16(1). doi: 10.1088/1752-7163/ac3c18. PMID: 34808607.

Link to full text: Levels of end-tidal carbon dioxide are low despite normal respiratory rate in individuals with long COVID

Abstract: ETCO2 and respiratory rate (RR) were measured in patients attending an outpatient clinic using an EMMA capnograph (Masimo Corporation, Irvine, CA). Approval for the collection and publication of this data was provided by the relevant Institutional Review Board (STUDY-20-001537). All patients were previously reviewed by a physician and diagnosed with confirmed (via PCR and/or antibody test) or probable (according to World Health Organization and Center for Disease Control and Prevention guidelines [6, 7]) past COVID-19 infection. The criteria for diagnosis of long COVID was the presence of persistent symptoms for at least 12 weeks after initial infection [2]. The capnograph was calibrated and a healthy control was used to check device readings at the commencement of each clinic. At the time of assessment, patients were seated and at rest, and had not performed other assessments or procedures immediately prior. Patients were instructed to breathe orally through the capnograph adapter at their resting rate and depth for a minimum of 15 s, and until the ETCO2 level was stable for a further period of at least 5 s. Data were analyzed using Stata (StataCorp LLC, TX), with descriptive statistics and Pearson correlation coefficient provided.

Title: Effects of decortication and carotid sinus nerve section on ventilation of the rat

Authors: Maskrey M, Megirian D, Nicol SC.

Journal: Respir Physiol. 1981 Mar;43(3):263-73. doi: 10.1016/0034-5687(81)90108-0. PMID: 6792671.

Link to PubMed: Effects of decortication and carotid sinus nerve section on ventilation of the rat

Abstract: The effect on ventilation of exposure to hypoxic, hypercapnic and hypoxic/hypercapnic gas mixtures was studied before and after functional decortication of intact rats and rats in which the carotid chemoreceptors had been disconnected. Unanaesthetized rats responded to both hypoxia and hypercapnia with an increase in minute ventilation (V) through increases in both frequency (f) and tidal volume (VT). Decortication led to a greater V response to CO2. This was through an effect on f, rather than VT. Carotid sinus nerve section (CSNS) caused a lessening in the V response to gas mixtures, f and VT being equally affected. Decortication, following CSNS, increased the V response but this time through increased VT rather than f. This effect on VT was not specific to any particular gas mixture. It is concluded that the carotid body chemoreceptors, together with the bulbopontine rate controller, influence the response to CO2. It is further suggested that this integration takes place in the reticular formation and is normally under some degree of inhibition from the cerebral cortex.

Title: CO2, brainstem chemoreceptors and breathing

Authors: Nattie E.

Journal: Prog Neurobiol. 1999 Nov;59(4):299-331. doi: 10.1016/s0301-0082(99)00008-8. PMID: 10501632.

Link to full text: CO2, brainstem chemoreceptors and breathing

Abstract: The regulation of breathing relies upon chemical feedback concerning the levels of CO2 and O2. The carotid bodies, which detect O2, provide tonic excitation to brainstem respiratory neurons under normal conditions and dramatic excitation if O2 levels fall. Feedback for CO2 involves the carotid body and receptors in the brainstem, central chemoreceptors. Small increases in CO2 produce large increases in breathing. Decreases in CO2 below normal can, in sleep and anesthesia, decrease breathing, even to apnea. Central chemoreceptors, once thought localized to the surface of the ventral medulla, are likely distributed more widely with sites presently identified in the: (1) ventrolateral medulla; (2) nucleus of the solitary tract; (3) ventral respiratory group; (4) locus ceruleus; (5) caudal medullary raphé; and (6) fastigial nucleus of the cerebellum. Why so many chemoreceptor sites? Hypotheses, some with supporting data, include the following. Geographical specificity; all regions of the brainstem with respiratory neurons contain chemoreceptors. Stimulus intensity; some sites operate in the physiological range of CO2 values, others only with more extreme changes. Stimulus specificity; CO2 or pH may be sensed by multiple mechanisms. Temporal specificity; some sites respond more quickly to changes on blood or brain CO2 or pH. Syncytium; chemosensitive neurons may be connected via low resistance, gap junctions. Arousal state: sites may vary in effectiveness and importance dependent on state of arousal. Overall, as judged by experiments of nature, and in the laboratory, central chemoreceptors are critical for adequate breathing in sleep, but other aspects of the control system can maintain breathing in wakefulness.

Title: Ventilatory response of decorticate and decerebrate cats to hypoxia and CO2

Authors: Tenney SM, Ou LC.

Journal: Respir Physiol. 1977 Feb;29(1):81-92. doi: 10.1016/0034-5687(77)90119-0. PMID: 847311.

Link to PubMed: Ventilatory response of decorticate and decerebrate cats to hypoxia and CO2

Abstract: The steady state ventilatory response of normal, fully awake cats was studied under graded hypoxia (at PAO2 = 110, 55, 45 torr) with PACO2 controlled throughout at the resting, normoxic level and at +5 torr. Subsequently, either a mid-collicular decerebration or a decortication was performed, and the ventilatory studies were repeated. Respiratory frequency, tidal volume, and ventilation in the decerebrate state responded to hypoxia and hypercapnia in a manner indistinguishable from the control. The decorticate cats, however, exhibited an exaggerated response to hypoxia, principally the result of increased frequency. The negative hypoxic, hypercapnic interaction, characteristic of awake cats, was demonstrable in both the decerebrate and decorticate animals. The findings are interpreted as revealing coupled descending influences on the medullary respiratory centers in hypoxia--one that is facilitatory and originates in the diencephalon, and the other, inhibitory, from the cerebrum. The significance of this suprapontine system in normal hypoxic ventilatory control is discussed.

Title: Air hunger' from increased Pco2 persists after complete neuromuscular block in humans

Authors: Banzett RB, Lansing RW, Brown R, Topulos GP, Yager D, Steele SM, Londoño B, Loring SH, Reid MB, Adams L, et al.

Journal: Respir Physiol. 1990 Jul;81(1):1-17. doi: 10.1016/0034-5687(90)90065-7. PMID: 2120757.

Link to PubMed: Air hunger' from increased Pco2 persists after complete neuromuscular block in humans

Abstract: The tolerance of totally curarized subjects for prolonged breath hold is viewed by many as evidence that respiratory muscle contraction is essential to generate the sensation of breathlessness. Although conflicting evidence exists, none of it was obtained during total neuromuscular block. We completely paralyzed four normal, unsedated subjects with vecuronium (a non-depolarizing neuromuscular blocker). Subjects were mechanically ventilated with hyperoxic gas mixtures at fixed rate and tidal volume. End-expiratory PCO2 (PETCO2) was varied surreptitiously by changing inspired PCO2. Subjects rated their respiratory discomfort or 'air hunger' every 45 sec. At low PETCO2 (median 35 Torr) they felt little or no air hunger. When PETCO2 was raised (median 44 Torr) all subjects reported severe air hunger. They had reported the same degree of air hunger at essentially the same PETCO2 before paralysis. When questioned afterwards all subjects said the sensation could be described by the terms 'air hunger', 'urge to breathe', and 'shortness of breath', and that is was like breath holding. They reported no fundamental difference in the sensation before and after paralysis. We conclude that respiratory muscle contraction is not important in the genesis of air hunger evoked by hypercapnia.

Title: Accuracy of respiratory symptom perception in different affective contexts

Authors: Bogaerts K, Notebaert K, Van Diest I, Devriese S, De Peuter S, Van den Bergh O.

Journal: J Psychosom Res. 2005 Jun;58(6):537-43. doi: 10.1016/j.jpsychores.2004.12.005. PMID: 16125521.

Link to PubMed: Accuracy of respiratory symptom perception in different affective contexts

Abstract: Objective: The accuracy of respiratory symptom perception was investigated in different affective contexts in participants (N=48) scoring high or low for negative affectivity (NA). Methods: Within-subject correlations were calculated between two subjective ratings and their respective physiological referent (the rating of "deeper breathing" and respiratory volume, and rating of "faster breathing" and breathing frequency) across nine consecutive breathing trials. Three different air mixtures were used: room air, air enriched with 7.5% CO(2), and with 10% CO(2). For half the participants, the trials were framed in a pleasant context, created by adding a pleasant odour to the air mixture in addition to information announcing pleasant feelings as a result of breathing the air mixtures. The other half received the trials in a distressing context: A foul smelling odour was added and the information announced unpleasant feelings. Results: High-NA persons were overall less accurate than were low-NA persons in the perception of respiratory volume. For breathing frequency, high-NA persons were significantly less accurate in the distressing condition than in the pleasant one, whereas for low-NA persons, the information frame did not matter. Conclusion: The study shows that the accuracy of respiratory symptom reports is reduced in high-NA persons, especially in a distressing context.

Title: A prospective examination of distress tolerance and early smoking lapse in adult self-quitters

Authors: Brown RA, Lejuez CW, Strong DR, Kahler CW, Zvolensky MJ, Carpenter LL, Niaura R, Price LH.

Journal: Nicotine Tob Res. 2009 May;11(5):493-502. doi: 10.1093/ntr/ntp041. Epub 2009 Apr 16. PMID: 19372572; PMCID: PMC2671465.

Link to full text: A prospective examination of distress tolerance and early smoking lapse in adult self-quitters

Abstract: Introduction: A significant percentage of smokers attempting cessation lapse to smoking within a matter of days, and current models of relapse devote insufficient attention to such early smoking lapse. Studies attempting to relate severity of nicotine withdrawal symptoms to short-term smoking cessation outcomes have yielded equivocal results. How one reacts to the discomfort of nicotine withdrawal and quitting smoking (i.e., distress tolerance) may be a more promising avenue of investigation with important treatment implications. Methods: The present investigation examined distress tolerance and early smoking lapse using a prospective design. Participants were 81 adult daily smokers recruited through newspaper advertisements targeted at smokers planning to quit smoking without assistance (i.e., no pharmacotherapy or psychosocial treatment; 42 males and 39 females; mean age = 42.6 years, SD = 12.20). Results: As hypothesized, both greater breath-holding duration and carbon dioxide-enriched air persistence were associated with a significantly lower risk of smoking lapse following an unaided quit attempt. These effects were above and beyond the risk associated with levels of nicotine dependence, education, and history of major depressive disorder, suggesting that distress tolerance and task persistence may operate independently of risk factors such as nicotine dependence and depressive history. In contrast to expectation, persistence on the Paced Auditory Serial Addition Test (a psychological challenge task) was not a significant predictor of earlier smoking lapse. Discussion: These results are discussed in relation to refining theoretical models of the role of distress tolerance in early smoking lapse and the utility of such models in the development of specialized treatment approaches for smoking cessation.

Title: Distress Tolerance and Duration of Past Smoking Cessation Attempts

Authors: Brown RA, Lejuez CW, Kahler CW, Strong DR.

Journal: J Abnorm Psychol. 2002 Feb;111(1):180-5. PMID: 11866171.

Link to PubMed: Distress Tolerance and Duration of Past Smoking Cessation Attempts

Abstract: The present study tested the hypothesis that limited ability to tolerate physical and psychological distress is associated with early relapse from smoking cessation. Specifically, the authors exposed 16 current smokers who had failed to sustain any previous quit attempt for more than 24 hr (immediate relapsers) and 16 smokers with at least 1 sustained quit attempt of 3 months or longer (delayed relapsers) to psychological (mental arithmetic) and physical (carbon dioxide inhalation-breath holding) stressors. Relative to delayed relapsers, immediate relapsers were characterized by higher baseline levels of affective vulnerability, by greater levels of dysphoria and urge to smoke after 12 hr of nicotine deprivation, and by less task persistence on the stressors, suggesting that these may be risk factors for early lapse in the context of quitting smoking.

Title: Rebreathing to cope with hyperventilation: experimental tests of the paper bag method

Authors: van den Hout MA, Boek C, van der Molen GM, Jansen A, Griez E.

Journal: J Behav Med. 1988 Jun;11(3):303-10. doi: 10.1007/BF00844435. PMID: 3139884.

Link to PubMed: Rebreathing to cope with hyperventilation: experimental tests of the paper bag method

Abstract: To explore if and how the common rebreathing (paper bag) approach to hyperventilation works, two experiments were carried out. In the first experiment, 12 normal volunteers, aware of the common physiological rebreathing rationale, were twice asked to overbreath intensely and then either to rebreath or to restart normal ventilation. Alveolar CO2 increased more quickly and physical symptoms disappeared earlier in the rebreathing condition. The second experiment had a similar design; however, this time the subjects were led to believe that, after both hyperventilation provocation tests, they were rebreathing in a semiclosed tube system. On one of the occasions, the tube system was, in fact, open. The CO2 restoration again differed in the two conditions. In this second experiment, the moment of symptom disappearance was not significantly earlier in the rebreathing condition. The combined results of the studies suggest that expectation and suggestion play a role in the effects of rebreathing approaches on hyperventilation.

Title: Ventilatory response to CO2. II. Studies in neurotic psychiatric patients and practitioners of transcendental meditation

Authors: Singh BS.

Journal: Psychosom Med. 1984 Jul-Aug;46(4):347-62. doi: 10.1097/00006842-198407000-00004. PMID: 6435149.

Link to PubMed: Ventilatory response to CO2. II. Studies in neurotic psychiatric patients and practitioners of transcendental meditation

Abstract: The prominence of respiratory symptoms in patients with neurotic psychiatric disorders is noted and the literature on the control of respiration is reviewed to attempt to explain this finding. A previous study demonstrated a positive correlation between the ventilatory response to CO2 (S) and neurotic personality traits in a group of normal subjects. This study attempted to follow up this finding and hypothesized that a group of neurotically disturbed patients would have a higher S value and a group of individuals who practiced a calming technique such as transcendental meditation (TM) would have a lower S value than normal subjects. The second hypothesis was confirmed, but not the first, in that the neurotically disturbed patients had the lowest mean values for S of the three groups, rather than the highest. Particular characteristics of the sample of psychiatric patients cast doubt, however, on the validity of this finding. Three additional findings of this study were that anxious, depressive, and hyperventilating subject groups were no different from one another in terms of S values; that very experienced TM practitioners (sidhas) could significantly lower their ventilatory response to CO2 in the meditating state as compared to the nonmeditating alert state; and that the S value did not increase in two male subjects with endogenous depression after successful treatment with electroconvulsive therapy.

Title: Pattern of breathing and ventilatory response to CO2 in subjects practicing hatha-yoga

Authors: Stănescu DC, Nemery B, Veriter C, Maréchal C.

Journal: J Appl Physiol Respir Environ Exerc Physiol. 1981 Dec;51(6):1625-9. doi: 10.1152/jappl.1981.51.6.1625. PMID: 6798002.

Link to PubMed: Pattern of breathing and ventilatory response to CO2 in subjects practicing hatha-yoga

Abstract: WE studied eight Belgian subjects well advanced in the practice of hatha-yoga and compared them with eight sex-, age-, and height-matched control subjects. Practice of yoga (range 4-12 yr) involves control of posture and manipulation of breathing, including slow near-vital capacity maneuvers accompanied by apnea at end inspiration and end expiration. Average values for the yoga and the control group (in parentheses) are as follows: ventilation (VE) 5.53 1 X min-1 (7.07); tidal volume (VT), 1.03 liters (0.56); rate of breathing, 5.5 min-1 (13.4); end-tidal PCO2, 39.0 Torr (35.3). All differences are significant (P less than 0.05). Ventilatory response to CO2 (rebreathing technique) was significantly lower in the yoga group (P less than 0.01). The regression relating VE to VT during rebreathing of CO2 was VE = 8.1 (VT - 0.23) for the yoga group and VE = 15.8 (VT - 0.16) for the control group (P less than 0.005). We attribute these changes to chronic manipulation of respiration.

Title: Effect of transcendental meditation on breathing and respiratory control

Authors: Wolkove N, Kreisman H, Darragh D, Cohen C, Frank H.

Journal: J Appl Physiol Respir Environ Exerc Physiol. 1984 Mar;56(3):607-12. doi: 10.1152/jappl.1984.56.3.607. PMID: 6423589.

Link to PubMed: Effect of transcendental meditation on breathing and respiratory control

Abstract: We studied the effect of transcendental meditation (TM) on breathing using 16 experienced meditators and 16 control subjects. In controls, there was no significant difference in minute ventilation (VE), respiratory pattern, or hypercapnic response, whether breathing with eyes open-awake (CA), or with eyes closed-relaxing (CR). In meditators, VE decreased significantly during quiet breathing from 14.0 +/- 0.7 1/min with eyes open-awake (MA) to 12.4 +/- 0.6 1/min during meditation (MM) (P less than 0.02). The change in VE during meditation was due to a decrease in tidal volume (VT) resulting from a shortened inspiratory time (TI). Meditation was associated with a decreased response to progressive hypercapnia from 3.7 +/- 0.4 to 2.5 +/- 0.21 X min-1 X Torr-1 during MA and MM trials, respectively (P less than 0.01). During meditation VT was smaller at a given alveolar PCO2 than during MA studies because of a decrease in mean inspiratory flow rate (VT/TI). These observations suggest that an alteration in wakefulness, more subtle than sleep or the unconscious state, can significantly affect the chemical and neural regulation of breathing.

Title: Does a change in end-tidal carbon dioxide level predict high altitude mountain sickness?

Authors: Thundiyil JG, Williams AT, Little I, Stutsman M, Ladde JG, Papa L.

Journal: Heliyon. 2023 May 5;9(5):e16000. doi: 10.1016/j.heliyon.2023.e16000. PMID: 37215892; PMCID: PMC10192757.

Link to full text: Does a change in end-tidal carbon dioxide level predict high altitude mountain sickness?

Abstract: Background It is postulated that lack of hypoxic ventilatory response is a predictor for AMS. End-tidal carbon dioxide (ETCO2) is an accurate, noninvasive surrogate measure of ventilation. Objectives We sought to determine if changes in baseline ETCO2 predicts the development of AMS. Methods This prospective cohort study took place in three separate high-altitude hiking treks. Subjects included a convenience sample of hikers. Predictor variable was change in ETCO2 levels and outcome variable was AMS. Measurements of ETCO2 levels were obtained at the base and repeated daily at various elevations and the summit of each hike. Concurrently, hikers were scored for AMS by a trained investigator. We utilized correlation coefficients and developed a linear regression model for analysis. Results 21 subjects in 3 separate hikes participated: 10 ascended to 19,341 ft over 7 days, 6 ascended to 8900 ft in 1 day, and 4 ascended to 11,006 ft in 1 day. Mean age was 40 years, 67% were males, mean daily elevation gain was 2150 ft, and 5 hikers developed AMS. The correlation coefficients for ETCO2 and development of AMS were −0.46 (95%CI -0.33 to −0.57), and −0.77 (95%CI -0.71 to −0.83) for ETCO2 and altitude. ETCO2 predicted the development of symptoms better than the elevation with AUCs of 0.90 (95%CI 0.81–0.99) versus 0.64 (95%CI 0.45–0.83). An ETCO2 measurement of ≤22 mmHg was 100% sensitive and 60% specific for predicting AMS. Conclusions ETCO2 was strongly correlated with altitude and moderately correlated with AMS and it was a better predictor than altitude.

Title: Effect of carbon dioxide in acute mountain sickness: a rediscovery

Authors: Harvey TC, Raichle ME, Winterborn MH, Jensen J, Lassen NA, Richardson NV, Bradwell AR.

Journal: Lancet. 1988 Sep 17;2(8612):639-41. doi: 10.1016/s0140-6736(88)90465-5. Erratum in: Lancet 1988 Oct 1;2(8614):808. PMID: 2901515.

Link to PubMed: Effect of carbon dioxide in acute mountain sickness: a rediscovery

Abstract: The effect of adding CO2 to inhaled air in six subjects with acute mountain sickness was investigated during a medical expedition to 5400 m.3% CO2 in ambient air increased ventilation and resulted in a rise in PaO2 of between 24% and 40%. There was a 9-28% increase in PaCO2 and a reduction of the respiratory alkalosis normally seen at high altitude. Symptoms of acute mountain sickness were rapidly relieved. In three subjects cerebral blood flow increased by 17-39%, so that oxygen delivery to the brain would have been considerably improved. This study confirms earlier suggestions of the beneficial effect of CO2 inhalation at high altitude.

Title: Supplemental CO2 improves oxygen saturation, oxygen tension, and cerebral oxygenation in acutely hypoxic healthy subjects

Authors: Stepanek J, Dunn RA, Pradhan GN, Cevette MJ.

Journal: Physiol Rep. 2020 Jul;8(14):e14513. doi: 10.14814/phy2.14513. PMID: 32725791; PMCID: PMC7387889.

Link to full text: Supplemental CO2 improves oxygen saturation, oxygen tension, and cerebral oxygenation in acutely hypoxic healthy subjects

Abstract: Oxygen is viewed in medicine as the sole determinant of tissue oxygenation, though carbon dioxide homeostasis is equally important and clinically often ignored. The aims of this study were as follows: (a) to examine the effects of different acute hypoxic conditions on partial pressure of arterial oxygen ( PaO2), arterial oxygen saturation of hemoglobin (SaO2), and regional cerebral saturation of hemoglobin (rSO2 ); and (b) to evaluate supplemental CO2 as a tool to improve oxygenation in acutely hypoxic individuals. We hypothesized that exposure to gas mixtures with added CO2 would improve oxygenation in hypoxic human subjects. Twenty healthy subjects were exposed to 5-min intervals of two gas mixtures: hypoxic gas mixture containing 8% oxygen, and a CO2-enriched mixture containing 8% oxygen plus either 3% or 5% CO2. Ten subjects received the 3% CO2 -enriched mixture, and the remaining 10 subjects received the 5% CO2 -enriched mixture. The order of exposure was randomized. Blood gases, pulse oximetry, end-tidal CO2, and cerebral oximetry were measured. Compared to the purely hypoxic gas group, PaO2 was increased in the 3% and 5% CO2-enriched groups by 14.9 and 9.5 mmHg, respectively. Compared to pure hypoxia, SaO2 was increased in the 3% and 5% CO2-enriched groups by 16.8% and 12.9%, respectively. Both CO2-enriched gas groups had significantly higher end-exposure rSO2 and recovered to baseline rSO2 within 1 min, compared to the pure hypoxic gas group, which returned to baseline in 5 min. These results suggest that in acutely hypoxic subjects, CO2 supplementation improves blood oxygen saturation and oxygen tension as well as cerebral oxygenation measures.

Title: Rapid elimination of CO through the lungs: coming full circle 100 years on

Authors: Fisher JA, Iscoe S, Fedorko L, Duffin J.

Journal: Exp Physiol. 2011 Dec;96(12):1262-9. doi: 10.1113/expphysiol.2011.059428. Epub 2011 Oct 3. PMID: 21967899; PMCID: PMC3274699.

Link to full text: Rapid elimination of CO through the lungs: coming full circle 100 years on

Abstract: At the start of the 20th century, CO poisoning was treated by administering a combination of CO2 and O2 (carbogen) to stimulate ventilation. This treatment was reported to be highly effective, even reversing the deep coma of severe CO poisoning before patients arrived at the hospital. The efficacy of carbogen in treating CO poisoning was initially attributed to the absorption of CO2; however, it was eventually realized that the increase in pulmonary ventilation was the predominant factor accelerating clearance of CO from the blood. The inhaled CO2 in the carbogen stimulated ventilation but prevented hypocapnia and the resulting reductions in cerebral blood flow. By then, however, carbogen treatment for CO poisoning had been abandoned in favour of hyperbaric O2. Now, a half-century later, there is accumulating evidence that hyperbaric O2 is not efficacious, most probably because of delays in initiating treatment. We now also know that increases in pulmonary ventilation with O2-enriched gas can clear CO from the blood as fast, or very nearly as fast, as hyperbaric O2. Compared with hyperbaric O2, the technology for accelerating pulmonary clearance of CO with hyperoxic gas is not only portable and inexpensive, but also may be far more effective because treatment can be initiated sooner. In addition, the technology can be distributed more widely, especially in developing countries where the prevalence of CO poisoning is highest. Finally, early pulmonary CO clearance does not delay or preclude any other treatment, including subsequent treatment with hyperbaric O2.

Title: A randomized controlled trial of theophylline versus CO2 inhalation for treating apnea of prematurity

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

Journal: J Pediatr. 2008 Oct;153(4):513-8. doi: 10.1016/j.jpeds.2008.04.025. Epub 2008 Jun 4. PMID: 18534618.

Link to PubMed: A randomized controlled trial of theophylline versus CO2 inhalation for treating apnea of prematurity

Abstract: Objective: To determine whether inhalation of 0.8% CO(2) in preterm infants decreases the duration and rate of apnea as effectively as or better than theophylline with fewer adverse side effects. Study design: A prospective, randomized, control study of 42 preterm infants of gestational age 27 to 32 weeks assigned to receive inhaled CO(2) (n = 21) or theophylline (n = 21). The study group had a mean (+/- standard error of the mean) birth weight of 1437 +/- 57 g, gestational age of 29.4 +/- 0.3 weeks, and postnatal age of 43 +/- 4 days. After a control period, 0.8% CO(2) or theophylline was given for 2 hours, followed by a recovery period. Results: In the CO(2) group, apneic time and rate decreased significantly, from 9.4 +/- 1.6 seconds/minute and 94 +/- 15 apneic episodes/hour to 3.0 +/- 0.5 seconds/minute and 34 +/- 5 apneic episodes/hour. In the theophylline group, apneic time and rate decreased significantly, from 8 +/- 1 seconds/minute and 80 +/- 8 apneic episodes/hour to 2.5 +/- 0.4 seconds/minute and 28 +/- 3 apneic episodes/hour. Cerebral blood flow velocity (CBFV) decreased only during theophylline administration. Conclusions: Our findings suggest that inhaled low (0.8%) CO(2) concentrations in preterm infants is at least as effective as theophylline in decreasing the duration and number of apneic episodes, has fewer side effects, and causes no changes in CBFV. We speculate that CO(2) may be a better treatment for apnea of prematurity than methylxanthines.

Title: A Modeling Study on Inspired CO2 Rebreathing Device for Sleep Apnea Treatment by Means of CFD Analysis and Experiment

Authors: Shokoueinejad, M., Pazouki, A., Levin, J. et al.

Journal: Journal of Medical and Biological Engineering. 37. 288-297. 10.1007/s40846-017-0223-7.

Link to Springer: A Modeling Study on Inspired CO2 Rebreathing Device for Sleep Apnea Treatment by Means of CFD Analysis and Experiment

Abstract: We present the device design, simulation, and measurement results of a therapy device that potentially prevents sleep apnea by slightly increasing inspired CO2 through added dead space (DS). The rationale for treatment of sleep apnea with CO2 manipulation is based on two recently reported premises: (i) preventing transient reductions in PaCO2 will prevent the patient from reaching their apneic threshold, thereby preventing “central” apnea and instabilities in respiratory motor output; and (ii) raising PaCO2 and end-tidal CO2, even by a minimal amount, provides a strong recruitment of upper airway dilator muscles, thereby preventing airway obstruction. We have also provided the simulation results, obtained from solving the Navier–Stokes (NS) equations within the device volume. Therein, the NS equations are coupled with a convection–diffusion equation that represents the transport of CO2 in the device, thus enabling the transient simulation of CO2 propagation. Using this procedure, a prototype of variable volume dead space reservoir device was designed. Volumetric factors influencing carbon dioxide increases in the added reservoir (open-ended DS) were investigated. The maximum/minimum amount of CO2 concentration were obtained for the maximum/minimum device volume; 3.4 and 2.4 mol/m3 for the DS volumes of 1.2 and 0.5 × 10−3 m3, respectively. In all case studies, the CO2 buildup reached a plateau after approximately 20 breathing cycles. The experimental measurement results are in agreement with the simulation and numerical results obtained using the proposed simplified modeling technique, with a maximum relative error of 3.5%.

Title: Oxidative Stress in the Lung - The Essential Paradox

Authors: Rogers LK, Cismowski MJ.

Journal: Curr Opin Toxicol. 2018 Feb;7:37-43. doi: 10.1016/j.cotox.2017.09.001. Epub 2017 Sep 19. PMID: 29308441; PMCID: PMC5754020.

Link to full text: Oxidative Stress in the Lung - The Essential Paradox

Abstract: As eukaryotic life evolved, so too did the need for a source of energy that meets the requirements of complex organisms. Oxygen provides this vast potential energy source, but the same chemical reactivity which provides this potential also can have detrimental effects. The lung evolved as an organ that can efficiently promote gas exchange for the entire organism but as such, the lung is highly susceptible to its external environment. Oxygen can be transformed through both enzymatic and non-enzymatic processes into reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can lead to protein, lipid, and DNA damage. Under normal conditions ROS/RNS concentrations are minimized through the activity of antioxidants located both intracellularly and in the epithelial lining fluid of the lung. Oxidative stress in the lung results when the antioxidant capacity is overwhelmed or depleted through external exposures, such as altered oxygen tension or air pollution, or internally. Internal sources of oxidative stress include systemic disease and the activation of resident cells and inflammatory cells recruited in response to an exposure or systemic response. Pulmonary responses to oxidative stress include activation of oxidases, lipid peroxidation, increases in nitric oxide, and autophagy. These internal and external exposures with the subsequent pulmonary responses contribute to development of diseases directly linked to oxidative stress. These include asthma, COPD, and lung cancers. While the vulnerability of the lung to oxidative stress is acknowledged, few effective preventative strategies or therapeutics are currently available.

Title: Oxidative stress and free radicals in COPD--implications and relevance for treatment

Authors: Domej W, Oettl K, Renner W.

Journal: Int J Chron Obstruct Pulmon Dis. 2014 Oct 17;9:1207-24. doi: 10.2147/COPD.S51226. PMID: 25378921; PMCID: PMC4207545.

Link to full text: Oxidative stress and free radicals in COPD--implications and relevance for treatment

Abstract: Oxidative stress occurs when free radicals and other reactive species overwhelm the availability of antioxidants. Reactive oxygen species (ROS), reactive nitrogen species, and their counterpart antioxidant agents are essential for physiological signaling and host defense, as well as for the evolution and persistence of inflammation. When their normal steady state is disturbed, imbalances between oxidants and antioxidants may provoke pathological reactions causing a range of nonrespiratory and respiratory diseases, particularly chronic obstructive pulmonary disease (COPD). In the respiratory system, ROS may be either exogenous from more or less inhalative gaseous or particulate agents such as air pollutants, cigarette smoke, ambient high-altitude hypoxia, and some occupational dusts, or endogenously generated in the context of defense mechanisms against such infectious pathogens as bacteria, viruses, or fungi. ROS may also damage body tissues depending on the amount and duration of exposure and may further act as triggers for enzymatically generated ROS released from respiratory, immune, and inflammatory cells. This paper focuses on the general relevance of free radicals for the development and progression of both COPD and pulmonary emphysema as well as novel perspectives on therapeutic options. Unfortunately, current treatment options do not suffice to prevent chronic airway inflammation and are not yet able to substantially alter the course of COPD. Effective therapeutic antioxidant measures are urgently needed to control and mitigate local as well as systemic oxygen bursts in COPD and other respiratory diseases. In addition to current therapeutic prospects and aspects of genomic medicine, trending research topics in COPD are presented. Keywords: antioxidants; chronic obstructive pulmonary disease; reactive nitrogen species; reactive oxygen species.

Title: Reactive oxygen species and mitochondria: A nexus of cellular homeostasis

Authors: Dan Dunn J, Alvarez LA, Zhang X, Soldati T.

Journal: Redox Biol. 2015 Dec;6:472-485. doi: 10.1016/j.redox.2015.09.005. Epub 2015 Sep 10. PMID: 26432659; PMCID: PMC4596921.

Link to full text: Reactive oxygen species and mitochondria: A nexus of cellular homeostasis

Abstract: Reactive oxygen species (ROS) are integral components of multiple cellular pathways even though excessive or inappropriately localized ROS damage cells. ROS function as anti-microbial effector molecules and as signaling molecules that regulate such processes as NF-kB transcriptional activity, the production of DNA-based neutrophil extracellular traps (NETs), and autophagy. The main sources of cellular ROS are mitochondria and NADPH oxidases (NOXs). In contrast to NOX-generated ROS, ROS produced in the mitochondria (mtROS) were initially considered to be unwanted by-products of oxidative metabolism. Increasing evidence indicates that mtROS have been incorporated into signaling pathways including those regulating immune responses and autophagy. As metabolic hubs, mitochondria facilitate crosstalk between the metabolic state of the cell with these pathways. Mitochondria and ROS are thus a nexus of multiple pathways that determine the response of cells to disruptions in cellular homeostasis such as infection, sterile damage, and metabolic imbalance. In this review, we discuss the roles of mitochondria in the generation of ROS-derived anti-microbial effectors, the interplay of mitochondria and ROS with autophagy and the formation of DNA extracellular traps, and activation of the NLRP3 inflammasome by ROS and mitochondria. Keywords: Autophagy; Immunity; Inflammasome; Mitochondria; Neutrophil extracellular traps; Reactive oxygen species.

Title: Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Authors: Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK.

Journal: Circ Res. 2018 Mar 16;122(6):877-902. doi: 10.1161/CIRCRESAHA.117.311401. PMID: 29700084; PMCID: PMC5926825.

Link to full text: Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Abstract: Reactive oxygen species (ROS) are well known for their role in mediating both physiological and pathophysiological signal transduction. Enzymes and subcellular compartments that typically produce ROS are associated with metabolic regulation, and diseases associated with metabolic dysfunction may be influenced by changes in redox balance. In this review, we summarize the current literature surrounding ROS and their role in metabolic and inflammatory regulation, focusing on ROS signal transduction and its relationship to disease progression. In particular, we examine ROS production in compartments such as the cytoplasm, mitochondria, peroxisome, and endoplasmic reticulum and discuss how ROS influence metabolic processes such as proteasome function, autophagy, and general inflammatory signaling. We also summarize and highlight the role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke. In order to develop therapies that target oxidative signaling, it is vital to understand the balance ROS signaling plays in both physiology and pathophysiology, and how manipulation of this balance and the identity of the ROS may influence cellular and tissue homeostasis. An increased understanding of specific sources of ROS production and an appreciation for how ROS influence cellular metabolism may help guide us in the effort to treat cardiovascular diseases. Keywords: cardiovascular diseases; inflammation; metabolism; oxidative stress; signal transduction.

Title: The Effects of Hyperbaric Oxygenation on Oxidative Stress, Inflammation and Angiogenesis

Authors: De Wolde SD, Hulskes RH, Weenink RP, Hollmann MW, Van Hulst RA.

Journal: Biomolecules. 2021 Aug 14;11(8):1210. doi: 10.3390/biom11081210. PMID: 34439876; PMCID: PMC8394403.

Link to full text: The Effects of Hyperbaric Oxygenation on Oxidative Stress, Inflammation and Angiogenesis

Abstract: Hyperbaric oxygen therapy (HBOT) is commonly used as treatment in several diseases, such as non-healing chronic wounds, late radiation injuries and carbon monoxide poisoning. Ongoing research into HBOT has shown that preconditioning for surgery is a potential new treatment application, which may reduce complication rates and hospital stay. In this review, the effect of HBOT on oxidative stress, inflammation and angiogenesis is investigated to better understand the potential mechanisms underlying preconditioning for surgery using HBOT. A systematic search was conducted to retrieve studies measuring markers of oxidative stress, inflammation, or angiogenesis in humans. Analysis of the included studies showed that HBOT-induced oxidative stress reduces the concentrations of pro-inflammatory acute phase proteins, interleukins and cytokines and increases growth factors and other pro-angiogenesis cytokines. Several articles only noted this surge after the first HBOT session or for a short duration after each session. The anti-inflammatory status following HBOT may be mediated by hyperoxia interfering with NF-κB and IκBα. Further research into the effect of HBOT on inflammation and angiogenesis is needed to determine the implications of these findings for clinical practice. Keywords: angiogenesis; hyperbaric oxygen therapy; hyperbaric oxygenation; inflammation; neovascularization; oxidative stress.

Title: The Role of Reactive-Oxygen-Species in Microbial Persistence and Inflammation

Authors: Spooner R, Yilmaz O.

Journal: Int J Mol Sci. 2011 Jan 13;12(1):334-52. doi: 10.3390/ijms12010334. PMID: 21339989; PMCID: PMC3039955.

Link to full text: The Role of Reactive-Oxygen-Species in Microbial Persistence and Inflammation

Abstract: The mechanisms of chronic infections caused by opportunistic pathogens are of keen interest to both researchers and health professionals globally. Typically, chronic infectious disease can be characterized by an elevation in immune response, a process that can often lead to further destruction. Reactive-Oxygen-Species (ROS) have been strongly implicated in the aforementioned detrimental response by host that results in self-damage. Unlike excessive ROS production resulting in robust cellular death typically induced by acute infection or inflammation, lower levels of ROS produced by host cells are increasingly recognized to play a critical physiological role for regulating a variety of homeostatic cellular functions including growth, apoptosis, immune response, and microbial colonization. Sources of cellular ROS stimulation can include "danger-signal-molecules" such as extracellular ATP (eATP) released by stressed, infected, or dying cells. Particularly, eATP-P2X(7) receptor mediated ROS production has been lately found to be a key modulator for controlling chronic infection and inflammation. There is growing evidence that persistent microbes can alter host cell ROS production and modulate eATP-induced ROS for maintaining long-term carriage. Though these processes have yet to be fully understood, exploring potential positive traits of these "injurious" molecules could illuminate how opportunistic pathogens maintain persistence through physiological regulation of ROS signaling. Keywords: NADPH oxidase; NLRX1; P2X7 receptor; Porphyromonas gingivalis; epithelium; extracellular ATP; microbial persistence; opportunistic pathogens; reactive-oxygen-species.

Title: Humming, Nitric Oxide and Paranasal Sinus Ventilation

Authors: Maniscalco, M.

Journal: Karolinska Institutet (Sweden), 2006.

Link to full text: Humming, Nitric Oxide and Paranasal Sinus Ventilation

Abstract: The paranasal sinuses are air-filled bony cavities surrounding the nose. They communicate with the nose via the sinus ostia through which fluid and gases pass in both directions. A proper ventilation is crucial for sinus integrity and blockage of the ostia is a major risk factor for development of sinusitis. In this thesis we have explored an entirely new approach to monitor sinus ventilation- the nasal humming test. We show in human studies in vivo and in a sinus/nasal model that the oscillating airflow generated during humming produce a dramatic increase in sinus ventilation. Interestingly, this increased gas exchange can be readily monitored on-line by simultaneously measuring the levels of the gas nitric oxide (NO) in nasally exhaled air. The sinuses constitute a major natural reservoir of NO and when gas-exchange increases during humming NO escapes rapidly into the nasal cavity thereby creating a highly reproducible peak in exhaled NO. When exploring the different factors that determine the humming peak in NO we found that sinus ostium size was the most important but the humming frequency also influenced the sinus NO release. In patients with severe nasal polyposis and completely blocked sinus ostia the humming peak in NO was abolished. Moreover, in patients with allergic rhinitis, absence of a NO peak was associated with endoscopic signs suggestive of ostial obstruction. In the last study we went on to study if an oscillating airflow could be used not only to wash a gas out from the sinuses but also to enhance passage of substances into the sinuses. Indeed, we found evidence of an increased intra-sinus drug deposition by adding a sounding airflow to an aerosol. In conclusion, the ventilation of the paranasal sinuses increases greatly when a person is humming; a finding that could have both diagnostic and therapeutic implications. Measurements of nasal NO during humming may represent a test of sinus ostialfunction. In addition, aerosol in combination with a sounding airflow could possibly be useful to increase the delivery of drugs into the paranasal sinuses.

Title: Exhaled nasal nitric oxide during humming: potential clinical tool in sinonasal disease?

Authors: Maniscalco M, Pelaia G, Sofia M.

Journal: Biomark Med. 2013 Apr;7(2):261-6. doi: 10.2217/bmm.13.11. PMID: 23547821.

Link to PubMed: Exhaled nasal nitric oxide during humming: potential clinical tool in sinonasal disease?

Abstract: The use of nasal nitric oxide (nNO) in sinonasal disease has recently been advocated as a potential tool to explore upper inflammatory airway disease. However, it is currently hampered by some factors including the wide range of measurement methods, the presence of various confounding factors and the heterogeneity of the study population. The contribution of nasal airway and paranasal sinuses communicating with the nose through the ostia represents the main confounding factor. There is accumulating evidence that nasal humming (which is the production of a tone without opening the lips or forming words) during nNO measurement increases nNO levels due to a rapid gas exchange in the paranasal sinuses. The aim of this review is to discuss the basic concepts and clinical applications of nNO assessment during humming, which represents a simple and noninvasive method to approach sinonasal disease.

Title: Strong humming for one hour daily to terminate chronic rhinosinusitis in four days: a case report and hypothesis for action by stimulation of endogenous nasal nitric oxide production

Authors: Eby GA.

Journal: Med Hypotheses. 2006;66(4):851-4. doi: 10.1016/j.mehy.2005.11.035. Epub 2006 Jan 10. PMID: 16406689.

Link to PubMed: Strong humming for one hour daily to terminate chronic rhinosinusitis in four days: a case report and hypothesis for action by stimulation of endogenous nasal nitric oxide production

Abstract: Rhinosinusitis is an inflammation or infection of the nose and air pockets (sinuses) above, below and between the eyes which connect with the back of the nose through tiny openings (ostia). Rhinosinusitis can be caused by bacteria, viruses, fungi (molds) and possibly by allergies. Chronic rhinosinusitis (CRS) is an immune disorder caused by fungi. The immune response produced by eosinophils causes the fungi to be attacked, which leads to damage of the sinus membranes, resulting in full-blown rhinosinusitis symptoms. Gaseous nitric oxide (NO) is naturally released in the human respiratory tract. The major part of NO found in exhaled air originates in the nasal airways, although significant production of NO also takes place in the paranasal sinuses. Proper ventilation is essential for maintenance of sinus integrity, and blockage of the ostium is a central event in pathogenesis of sinusitis. Concentrations of NO in the healthy sinuses are high. Nasal NO is known to be increased 15- to 20-fold by humming compared with quiet exhalation. NO is known to be broadly antifungal, antiviral and antibacterial. This case report shows that a subject hummed strongly at a low pitch ( approximately 130 Hz) for 1h (18 hums per minute) at bedtime the first night, and hummed 60-120 times 4 times a day for the following 4 days as treatment for severe CRS. The humming technique was described as being one that maximally increased intranasal vibrations, but less than that required to produce dizziness. The morning after the first 1-h humming session, the subject awoke with a clear nose and found himself breathing easily through his nose for the first time in over 1 month. During the following 4 days, CRS symptoms slightly reoccurred, but with much less intensity each day. By humming 60-120 times four times per day (with a session at bedtime), CRS symptoms were essentially eliminated in 4 days. Coincidentally, the subject's cardiac arrhythmias (PACs) were greatly lessened. It is hypothesized that strong, prolonged humming increased endogenous nasal NO production, thus eliminating CRS by antifungal means.

Title: The human ventilatory response to stress: rate or depth?

Authors: Tipton MJ, Harper A, Paton JFR, Costello JT.

Journal: J Physiol. 2017 Sep 1;595(17):5729-5752. doi: 10.1113/JP274596. Epub 2017 Jul 27. PMID: 28650070; PMCID: PMC5577533.

Link to full text: The human ventilatory response to stress: rate or depth?

Abstract: Many stressors cause an increase in ventilation in humans. This is predominantly reported as an increase in minute ventilation (V̇E). But, the same V̇E can be achieved by a wide variety of changes in the depth (tidal volume, VT ) and number of breaths (respiratory frequency, ƒR ). This review investigates the impact of stressors including: cold, heat, hypoxia, pain and panic on the contributions of ƒR and VT to V̇E to see if they differ with different stressors. Where possible we also consider the potential mechanisms that underpin the responses identified, and propose mechanisms by which differences in ƒR and VT are mediated. Our aim being to consider if there is an overall differential control of ƒR and VT that applies in a wide range of conditions. We consider moderating factors, including exercise, sex, intensity and duration of stimuli. For the stressors reviewed, as the stress becomes extreme V̇E generally becomes increased more by ƒR than VT . We also present some tentative evidence that the pattern of ƒR and VT could provide some useful diagnostic information for a variety of clinical conditions. In The Physiological Society's year of 'Making Sense of Stress', this review has wide-ranging implications that are not limited to one discipline, but are integrative and relevant for physiology, psychophysiology, neuroscience and pathophysiology.

Title: The physiological effects of slow breathing in the healthy human

Authors: Russo MA, Santarelli DM, O'Rourke D.

Journal: Breathe (Sheff). 2017 Dec;13(4):298-309. doi: 10.1183/20734735.009817. PMID: 29209423; PMCID: PMC5709795.

Link to full text: The physiological effects of slow breathing in the healthy human

Abstract: Slow breathing practices have been adopted in the modern world across the globe due to their claimed health benefits. This has piqued the interest of researchers and clinicians who have initiated investigations into the physiological (and psychological) effects of slow breathing techniques and attempted to uncover the underlying mechanisms. The aim of this article is to provide a comprehensive overview of normal respiratory physiology and the documented physiological effects of slow breathing techniques according to research in healthy humans. The review focuses on the physiological implications to the respiratory, cardiovascular, cardiorespiratory and autonomic nervous systems, with particular focus on diaphragm activity, ventilation efficiency, haemodynamics, heart rate variability, cardiorespiratory coupling, respiratory sinus arrhythmia and sympathovagal balance. The review ends with a brief discussion of the potential clinical implications of slow breathing techniques. This is a topic that warrants further research, understanding and discussion.

Title: Slow breathing for reducing stress: The effect of extending exhale

Authors: Birdee G, Nelson K, Wallston K, Nian H, Diedrich A, Paranjape S, Abraham R, Gamboa A.

Journal: Complement Ther Med. 2023 May;73:102937. doi: 10.1016/j.ctim.2023.102937. Epub 2023 Mar 5. PMID: 36871835; PMCID: PMC10395759.

Link to full text: Slow breathing for reducing stress: The effect of extending exhale

Abstract: Introduction: Slow breathing techniques are commonly used to reduce stress. While it is believed by mind-body practitioners that extending the exhale time relative to inhale increases relaxation, this has not been demonstrated.

Methods: We conducted a 12-week randomized, single-blinded trial among 100 participants to compare if yoga-based slow breathing with an exhale greater inhale versus an exhale equals inhale produces measurable differences in physiological and psychological stress among healthy adults.

Results: Participants mean individual instruction attendance was 10.7 ± 1.5 sessions out of 12 offered sessions. The mean weekly home practice was 4.8 ± 1.2 practices per week. There was no statistical difference between treatment groups for frequency of class attendance, home practice, or achieved slow breathing respiratory rate. Participants demonstrated fidelity to assigned breath ratios with home practice as measured by remote biometric assessments through smart garments (HEXOSKIN). Regular slow breathing practice for 12 weeks significantly reduced psychological stress as measured by PROMIS Anxiety (-4.85 S.D. ± 5.53, confidence interval [-5.60, -3.00], but not physiological stress as measured by heart rate variability. Group comparisons showed small effect size differences (d = 0.2) with further reductions in psychological stress and physiological stress from baseline to 12 weeks for exhale greater than inhale versus exhale equals inhale, however these differences were not statistically significant.

Conclusion: While slow breathing significantly reduces psychological stress, breath ratios do not have a significant differential effect on stress reduction among healthy adults.

Title: Respiratory alkalosis may impair the production of vitamin D and lead to significant morbidity, including the fibromyalgia syndrome

Authors: Lewis JM, Fontrier TH, Coley JL.

Journal: Med Hypotheses. 2017 May;102:99-101. doi: 10.1016/j.mehy.2017.03.013. Epub 2017 Mar 8. PMID: 28478843.

Link to PubMed: Respiratory alkalosis may impair the production of vitamin D and lead to significant morbidity, including the fibromyalgia syndrome

Abstract: Hyperventilation caused by physical and/or psychological stress may lead to significant respiratory alkalosis and an elevated systemic pH. The alkalotic pH may in turn suppress the normal renal release of phosphate into the urine, thereby interrupting the endogenous production of 1,25-dihydroxyvitamin D (calcitriol). This could cause a shortfall in its normal production, leading to a variety of adverse consequences. It might partially explain the pathogenesis of acute mountain sickness, a treatable disease characterized by severe hyperventilation secondary to the hypoxia of high altitude exposure. Milder degrees of hyperventilation due to different forms of stress may produce other conditions which share characteristics with acute mountain sickness. One of these may be the fibromyalgia syndrome, a chronic painful disorder for which no satisfactory treatment exists. Should fibromyalgia and acute mountain sickness have a common etiology, may they also share a common form of treatment? Evidence is presented to support this hypothesis.

Keywords: Acute mountain sickness; Fibromyalgia; Respiratory alkalosis; Vitamin D.

Title: Hyperventilation with Maintenance of Isocapnia. An "Old New" Method in Carbon Monoxide Intoxication

Authors: Sein Anand J, Schetz D, Waldman W, Wiśniewski M.

Journal: PLoS One. 2017 Jan 20;12(1):e0170621. doi: 10.1371/journal.pone.0170621. PMID: 28107437; PMCID: PMC5249161.

Link to full text: Hyperventilation with Maintenance of Isocapnia. An "Old New" Method in Carbon Monoxide Intoxication

Abstract: Introduction: Exposure to carbon monoxide (CO) is among the most common causes of acute and chronic poisonings worldwide. The crucial point of treatment of such acute poisonings is to eliminate CO from the body as fast as possible. There are currently two approaches to the management of the CO intoxication: hyperbaric oxygen therapy (HOT) and normobaric oxygen therapy (NOT). HOT is highly effective and capable of achieving the CO elimination half-time (T½) as low as 15 minutes. Unfortunately this method is expensive and not always readily available. The elimination of CO with the use of NOT (T½~70 min) is slower, but treatment can be started even on the site of the exposure and continued while the patient is transported to a hospital. The aim of the study was to evaluate the effectiveness of a method using therapeutic hyperventilation with maintenance of isocapnia (IH) in the elimination of CO in volunteers exposed to CO and to compare selected gasometric and respiratory parameters during IH with the values obtained during hyperventilation with pure oxygen ("non-isocapnic hyperventilation"-NIH).

Material and methods: The study involved 13 healthy, chronically-smoking volunteers. Each of them participated in two independent hyperventilation tests: IH and NIH. The levels of carboxyhemoglobin (COHb) and selected gasometric, cardiac and respiratory parameters were measured at 0, 10 and 20 minutes during both tests. Among 13 volunteers (8 women and 5 men) the initial COHb level was 5.0±1.5% (mean±SD) before the IH tests and 5.1±1.9% before the NIH tests (p>0.05). After 20 minutes of the procedures the mean COHb level was 2.9±0.9% for IH and 3.6±1.2% for NIH (p<0.01). The T½ of COHb was 29.6±12.2 min and 47.3±19.2 min respectively (p<0.01). After 10 minutes of NIH respiratory alkalosis was noted in 11 participants (84.6%). Such problem was not seen during the IH procedures. No serious adverse effects were recorded during either IH or NIH. Mild symptoms such as: dyspnea, headache and paresthesias were reported by 6 volunteers (46%) during both IH and NIH tests. It is worth noting that paresthesias were only reported during NIH, by 2 participants (15.4%).

Conclusions: The elimination T½ of CO during IH was comparable with the values reported during HOT, and lower than can be achieved with NOT or NIH. No serious adverse effects were reported during IH procedures. Further studies, especially direct comparisons with NOT and HOT, are necessary to evaluate the effectiveness of IH in the treatment of acute CO poisoning.

Title: Isocapnic hyperpnea accelerates carbon monoxide elimination

Authors: Fisher JA, Rucker J, Sommer LZ, Vesely A, Lavine E, Greenwald Y, Volgyesi G, Fedorko L, Iscoe S.

Journal: Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1289-92. doi: 10.1164/ajrccm.159.4.9804040. PMID: 10194179.

Link to full text: Isocapnic hyperpnea accelerates carbon monoxide elimination

Abstract: A major impediment to the use of hyperpnea in the treatment of CO poisoning is the development of hypocapnia or discomfort of CO2 inhalation. We examined the effect of nonrebreathing isocapnic hyperpnea on the rate of decrease of carboxyhemoglobin levels (COHb) in five pentobarbital-anesthetized ventilated dogs first exposed to CO and then ventilated with room air at normocapnia (control). They were then ventilated with 100% O2 at control ventilation, and at six times control ventilation without hypocapnia ("isocapnic hyperpnea") for at least 42 min at each ventilator setting. We measured blood gases and COHb. At control ventilation, the half-time for elimination of COHb (t1/2) was 212 +/- 17 min (mean +/- SD) on room air and 42 +/- 3 min on 100% O2. The t1/2 decreased to 18 +/- 2 min (p < 0.0005) during isocapnic hyperpnea. In two similarly prepared dogs treated with hyperbaric O2, the t1/2 were 20 and 28 min. We conclude that isocapnic hyperpnea more than doubles the rate of COHb elimination induced by normal ventilation with 100% O2. Isocapnic hyperpnea could improve the efficacy of the standard treatment of CO poisoning, 100% O2 at atmospheric or increased pressures.

Title: Accelerated ethanol elimination via the lungs

Authors: Klostranec JM, Vucevic D, Crawley AP, Venkatraghavan L, Sobczyk O, Duffin J, Sam K, Holmes R, Fedorko L, Mikulis DJ, Fisher JA.

Journal: Sci Rep. 2020 Nov 12;10(1):19249. doi: 10.1038/s41598-020-76233-9. PMID: 33184355; PMCID: PMC7665168.

Link to full text: Accelerated ethanol elimination via the lungs

Abstract: Ethanol poisoning is endemic the world over. Morbidity and mortality depend on blood ethanol levels which in turn depend on the balance between its rates of absorption and clearance. Clearance of ethanol is mostly at a constant rate via enzymatic metabolism. We hypothesized that isocapnic hyperpnea (IH), previously shown to be effective in acceleration of clearance of vapour anesthetics and carbon monoxide, would also accelerate the clearance of ethanol. In this proof-of-concept pilot study, five healthy male subjects were brought to a mildly elevated blood ethanol concentration (~ 0.1%) and ethanol clearance monitored during normal ventilation and IH on different days. IH increased elimination rate of ethanol in proportion to blood levels, increasing the elimination rate more than three-fold. Increased veno-arterial ethanol concentration differences during IH verified the efficacy of ethanol clearance via the lung. These data indicate that IH is a nonpharmacologic means to accelerate the elimination of ethanol by superimposing first order elimination kinetics on underlying zero order liver metabolism. Such kinetics may prove useful in treating acute severe ethanol intoxication.

Title: The treatment of acute alcoholism: with ten per cent carbon dioxide and ninety per cent oxygen inhalation

Authors: Robinson LJ, Selesnick S.

Journal: JAMA. 1935;105(22):1734–1738. doi:10.1001/jama.1935.02760480004002

Link to full text: The treatment of acute alcoholism: with ten per cent carbon dioxide and ninety per cent oxygen inhalation

Abstract: For many years the Fifth Medical Service of the Boston City Hospital has been in charge of almost all medical alcoholic patients admitted to this hospital. It is estimated that approximately 700 alcoholic patients are admitted to this service for treatment each year. The opportunity has been present, therefore, to study alcoholism in all its phases.
The acute alcoholic patient1 generally can be given a good prognosis as to recovery. For this reason, even when medical aid is sought for him, he receives little active therapy. In the paralytic stage of acute alcoholic poisoning, however, emergency treatment may be life -saving. Patients in this stage present a picture best described by Sollmann, who states that the symptoms are those of beginning medullary paralysis. Since carbon dioxide increased the respiratory excretion of alcohol, and since the oxidation of alcohol might be increased through the administration of oxygen, it is conceivable that the inhalation of a combination of 10 per cent carbon dioxide and 90 per cent oxygen mixture might accelerate recovery from acute alcoholic coma, especially of the paralytic state with respiratory depression and cyanosis. If it did no more than keep such a patient from dying of respiratory depression, it would, by keeping him alive, enable him to oxidize the alcohol himself. CONCLUSIONS: Acute alcoholic coma with dangerous respiratory depression, paralysis and cyanosis is a medical emergency. Death may be definitely prevented and recovery accelerated by inhalation of a mixture of 10 per cent carbon dioxide and 90 per cent oxygen for a length of time sufficient to reestablish and maintain normal respiration and color even after the inhalation is suspended.

Title: Carbon Dioixde in Anaesthesia

Authors: Wilson S.R.

Journal: BJA: British Journal of Anaesthesia, Volume 3, Issue 3, January 1926, Pages 112–118, https://doi.org/10.1093/bja/3.3.112

Link to full text: Carbon Dioixde in Anaesthesia

Abstract: All general anaesthetics are toxic agents in varying degrees and prone to produce undesirable after-effects on the patient. It is therefore advantageous to effect their elimination the moment their work is completed. Henderson and Haggard have investigated the rate of excretion of ether after general anaesthesia and provided us with accurate data on this subject. They found that half the total ether in the body was eliminated in the first half hour after the administration is stopped. Half the remainder is excreted during the next one to two hours, but complete elimination does not occur until one to two days. If it is possible to accelerate this process undesirable after-effects can be greatly reduced or completely avoided.
Now, if 5–6 per cent CO₂ be added to the oxygen pulmonary ventilation is increased two, three or four times. The writer has tested these experimental observations in actual clinical practice during the last two years with most gratifying results, both to himself and the patients concerned.

Title: Isocapnic hyperventilation provides early extubation after head and neck surgery: A prospective randomized trial.

Authors: Hallén K, Jildenstål P, Stenqvist O, Oras J, Ricksten SE, Lindgren S.

Journal: Acta Anaesthesiol Scand. 2018 Sep;62(8):1064-1071. doi: 10.1111/aas.13133. Epub 2018 Apr 19. PMID: 29671866.

Link to PubMed: Isocapnic hyperventilation provides early extubation after head and neck surgery: A prospective randomized trial.

Abstract: Background: Isocapnic hyperventilation (IHV) shortens recovery time after inhalation anaesthesia by increasing ventilation while maintaining a normal airway carbon dioxide (CO2)-level. One way of performing IHV is to infuse CO2 to the inspiratory limb of a breathing circuit during mechanical hyperventilation (HV). In a prospective randomized study, we compared this IHV technique to a standard emergence procedure (control).

Methods: Thirty-one adult ASA I-III patients undergoing long-duration (>3 hours) sevoflurane anaesthesia for major head and neck surgery were included and randomized to IHV-treatment (n = 16) or control (n = 15). IHV was performed at minute ventilation 13.6 ± 4.3 L/min and CO2 delivery, dosed according to a nomogram tested in a pilot study. Time to extubation and eye-opening was recorded. Inspired (FICO2) and expired (FETCO2) CO2 and arterial CO2 levels (PaCO2) were monitored. Cognition was tested preoperatively and at 20, 40 and 60 minutes after surgery.

Results: Time from turning off the vapourizer to extubation was 13.7 ± 2.5 minutes in the IHV group and 27.4 ± 6.5 minutes in controls (P < .001). Two minutes after extubation, PaCO2 was 6.2 ± 0.5 and 6.2 ± 0.6 kPa in the IHV and control group respectively. In 69% (IHV) vs 53% (controls), post-operative cognition returned to pre-operative values within 40 minutes after surgery (NS). Incidences of pain and nausea/vomiting did not differ between groups.

Conclusions: In this randomized trial comparing an IHV method with a standard weaning procedure, time to extubation was reduced with 50% in the IHV group. The described IHV method can be used to decrease emergence time from inhalation anaesthesia.

Title: Isocapnic hyperventilation shortens washout time for sevoflurane - an experimental in vivo study

Authors: Hallén K, Stenqvist O, Ricksten SE, Lindgren S.

Journal: Acta Anaesthesiol Scand. 2016 Oct;60(9):1261-9. doi: 10.1111/aas.12761. Epub 2016 Jul 10. PMID: 27396945.

Link to PubMed: Isocapnic hyperventilation shortens washout time for sevoflurane - an experimental in vivo study

Abstract: Background: Isocapnic hyperventilation (IHV) is a method that fastens weaning from inhalation anaesthesia by increasing airway concentration of carbon dioxide (CO2 ) during hyperventilation (HV). In an animal model, we evaluated a technique of adding CO2 directly to the breathing circuit of a standard anaesthesia apparatus.

Methods: Eight anaesthetised pigs weighing 28 ± 2 kg were intubated and mechanically ventilated. From a baseline ventilation of 5 l/min, HV was achieved by doubling minute volume and fresh gas flow. Respiratory rate was increased from 15 to 22/min. The CO2 absorber was disconnected and CO2 was delivered (DCO2 ) to the inspiratory limb of a standard breathing circuit via a mixing box. Time required to decrease end-tidal sevoflurane concentration from 2.7% to 0.2% was defined as washout time. Respiration and haemodynamics were monitored by blood gas analysis, spirometry, electric impedance tomography and pulse contour analysis.

Results: A DCO2 of 261 ± 19 ml/min was necessary to achieve isocapnia during HV. The corresponding FICO2 -level remained stable at 3.1 ± 0.3%. During IHV, washout of sevoflurane was three times faster, 433 ± 135 s vs. 1387 ± 204 s (P < 0.001). Arterial CO2 tension and end-tidal CO2 , was 5.2 ± 0.4 kPa and 5.6 ± 0.4%, respectively, before IHV and 5.1 ± 0.3 kPa and 5.7 ± 0.3%, respectively, during IHV.

Conclusions: In this experimental in vivo model of isocapnic hyperventilation, the washout time of sevoflurane anaesthesia was one-third compared to normal ventilation. The method for isocapnic hyperventilation described can potentially be transferred to a clinical setting with the intention to decrease emergence time from inhalation anaesthesia.

Title: A simple method for isocapnic hyperventilation evaluated in a lung model

Authors: Hallén K, Stenqvist O, Ricksten SE, Lindgren S.

Journal: Acta Anaesthesiol Scand. 2016 May;60(5):597-606. doi: 10.1111/aas.12674. Epub 2015 Dec 21. PMID: 26688296.

Link to PubMed: A simple method for isocapnic hyperventilation evaluated in a lung model

Abstract: Background: Isocapnic hyperventilation (IHV) has the potential to increase the elimination rate of anaesthetic gases and has been shown to shorten time to wake-up and post-operative recovery time after inhalation anaesthesia. In this bench test, we describe a technique to achieve isocapnia during hyperventilation (HV) by adding carbon dioxide (CO2) directly to the breathing circuit of a standard anaesthesia apparatus with standard monitoring equipment.

Methods: Into a mechanical lung model, carbon dioxide was added to simulate a CO2 production (V(CO2)) of 175, 200 and 225 ml/min. Dead space (V(D)) volume could be set at 44, 92 and 134 ml. From baseline ventilation (BLV), HV was achieved by doubling the minute ventilation and fresh gas flow for each level of V(CO2), and dead space. During HV, CO2 was delivered (D(CO2)) by a precision flow meter via a mixing box to the inspiratory limb of the anaesthesia circuit to achieve isocapnia.

Results: During HV, the alveolar ventilation increased by 113 ± 6%. Tidal volume increased by 20 ± 0.1% during IHV irrespective of V(D) and V(CO2) level. D(CO2) varied between 147 ± 8 and 325 ± 13 ml/min. Low V(CO2) and large V(D) demanded a greater D(CO2) administration to achieve isocapnia. The FICO2 level during IHV varied between 2.3% and 3.3%.

Conclusion: It is possible to maintain isocapnia during HV by delivering carbon dioxide through a standard anaesthesia circuit equipped with modern monitoring capacities. From alveolar ventilation, CO2 production and dead space, the amount of carbon dioxide that is needed to achieve IHV can be estimated.

Title: Evaluation of a method for isocapnic hyperventilation: a clinical pilot trial

Authors: Hallén K, Jildenstål P, Stenqvist O, Ricksten SE, Lindgren S.

Journal: Acta Anaesthesiol Scand. 2018 Feb;62(2):186-195. doi: 10.1111/aas.13008. Epub 2017 Oct 16. PMID: 29034967.

Link to PubMed: Evaluation of a method for isocapnic hyperventilation: a clinical pilot trial

Abstract: Background: Isocapnic hyperventilation (IHV) is a method that shortens time to extubation after inhalation anaesthesia using hyperventilation (HV) without lowering airway CO2 . In a clinical trial on patients undergoing long-duration sevoflurane anaesthesia for major ear-nose-throat (ENT) surgery, we evaluated the utility of a technique for CO2 delivery (DCO2 ) to the inspiratory limb of a closed breathing circuit, during HV, to achieve isocapnia.

Methods: Fifteen adult ASA 1-3 patients were included. After end of surgery, mechanical HV was started by doubling baseline minute ventilation. Simultaneously, CO2 was delivered and dosed using a nomogram developed in a previous experimental study. Time to extubation and eye opening was recorded. Inspired (FICO2 ) and expired (FETCO2 ) CO2 and arterial CO2 levels were monitored during IHV. Cognition was tested pre-operatively and at 20, 40 and 60 min after surgery.

Results: A DCO2 of 285 ± 45 ml/min provided stable isocapnia during HV (13.5 ± 4.1 l/min). The corresponding FICO2 level was 3.0 ± 0.3%. Time from turning off the vaporizer (1.3 ± 0.1 MACage) to extubation (0.2 ± 0.1 MACage) was 11.3 ± 1.8 min after 342 ± 131 min of anaesthesia. PaCO2 and FETCO2 remained at normal levels during and after IHV. In 85% of the patients, post-operative cognition returned to pre-operative values within 60 min.

Conclusions: In this cohort of patients, a DCO2 nomogram for IHV was validated. The patients were safely extubated shortly after discontinuing long-term sevoflurane anaesthesia. Perioperatively, there were no adverse effects on arterial blood gases or post-operative cognition. This technique for IHV can potentially be used to decrease emergence time from inhalation anaesthesia.

Title: Impact of breathing patterns on the quality of life of 9- to 10-year-old schoolchildren

Authors: Leal RB, Gomes MC, Granville-Garcia AF, Goes PS, de Menezes VA.

Journal: Am J Rhinol Allergy. 2016 Sep;30(5):147-52. doi: 10.2500/ajra.2016.30.4363. PMID: 27657891.

Link to PubMed: Impact of breathing patterns on the quality of life of 9- to 10-year-old schoolchildren

Abstract: Background: Mouth breathing can cause a set of changes in craniofacial growth and development, with esthetic, functional, and psychological repercussions.

Objective: To determine the impact of mouth breathing on the quality of life of schoolchildren.

Methods: A school-based, cross-sectional study was conducted with 1911 children ages 9 and 10 years in the city of Recife, Brazil. The children answered the Mouth Breather Quality of Life questionnaire and a questionnaire that addressed sociodemographic data and health-related aspects. Clinical examinations were performed by an examiner who had undergone a training and calibration process for the diagnosis of mouth breathing (kappa = 0.90). Descriptive statistics were conducted to characterize the sample. Statistical analysis involved the Student's t-test and the F test (analysis of variance) (alpha = 5%).

Results: The prevalence of mouth breathing was 54.81%. Children with oral breathing demonstrated a poorer quality of life in comparison with children with nasal breathing (p < 0.001). The following variables were significantly associated with a poorer quality of life among the children with mouth breathing: a younger age (p < 0.001) and the use of medication (p = 0.002).

Conclusion: Based on the present findings, children with the mouth-breathing pattern experience a greater negative impact on quality of life in comparison with those with the nose-breathing pattern. Thus, the early diagnosis and treatment of this clinical condition are fundamental to minimizing the consequences of mouth breathing on the quality of life of schoolchildren with respiration disorders.

Title: Structural and physiological age-associated changes in aging lungs

Authors: Miller MR.

Journal: Semin Respir Crit Care Med. 2010 Oct;31(5):521-7. doi: 10.1055/s-0030-1265893. Epub 2010 Oct 12. PMID: 20941653.

Link to PubMed: Structural and physiological age-associated changes in aging lungs

Abstract: The tissues of the lungs undergo changes with age that lead to an increase in alveolar size without any destruction of alveolar walls. This lowers the alveolar surface tension and so reduces the elastic recoil of the lungs, which in turn causes a reduction in maximum achievable flow in the airways during the breathing cycle. Muscle performance diminishes with age and the chest wall becomes stiffer, which together lead to an increased residual volume and also counter the possible increase in total lung capacity (TLC) from the reduced elastic recoil. Exercise performance falls with age, with a small decrease in arterial oxygenation that stabilizes over the age of 70 years. Predicting lung function for the elderly is not easy, and basing clinical decisions on percent of predicted may lead to age, sex, and height bias. Focusing on what function remains can allow survival predictions to guide decisions on treatment options.

Title: Relationship between breath-hold time and physical performance in patients with cystic fibrosis

Authors: Barnai M, Laki I, Gyurkovits K, Angyan L, Horvath G.

Journal: Eur J Appl Physiol. 2005 Oct;95(2-3):172-8. doi: 10.1007/s00421-005-1350-3. Epub 2005 Jul 9. PMID: 16007450.

Link to PubMed: Relationship between breath-hold time and physical performance in patients with cystic fibrosis

Abstract: Rehabilitation including physiotherapy is an important part of the treatment used to help improve the quality of life of patients with cystic fibrosis (CF). The aim of this study was to determine the value of the breath-hold time as an index of exercise tolerance in patients with CF. Eighteen patients in different states of CF were included. The breath-hold time was measured in all patients. The fitness level was assessed by means of a progressive exercise test on a cycle-ergometer. During the test, oxygen uptake (VO(2)) and carbon dioxide elimination (VCO(2)) were measured breath by breath. The VO(2) and working capacity (WC) were computed at the anaerobic threshold (AT) and at peak. Duration of breath-hold was 24.7 +/- 2.87 (mean +/- SEM) seconds, varying between 10 and 58. The breath-hold time (BHT) displayed a significant correlation with VO(2) (r = 0.898), WC (r = 0.899) at the AT, and the peak VO(2) (r = 0.895). Regression equations were: VO(2) at the AT (ml/kg) = 5.53 + 0.42 x BHT and WC at the AT (watt/kg) = 0.56 + 0.38 x BHT Our results suggest that the voluntary breath-hold time might be a useful index for prediction of the exercise tolerance of CF patients.

Title: Physiology, Pulmonary Circulatory System

Authors: Jain V, Bordes SJ, Bhardwaj A.

Journal: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

Link to PubMed: Physiology, Pulmonary Circulatory System

Abstract: Pulmonary circulation includes a vast network of arteries, veins, and lymphatics that function to exchange blood and other tissue fluids between the heart, the lungs, and back. They are designed to perform certain specific functions that are unique to the pulmonary circulation, such as ventilation and gas exchange. The pulmonary circulation receives the entirety of the cardiac output from the right heart and is a low pressure, low resistance system due to its parallel capillary circulation. The system can be divided into the following components:

The arterial circuit arises from the main pulmonary artery arising from the right ventricle and runs a course of only 5 cm before dividing into right and left main branches and many subsequent branches to form an extensive network of small arteries, arterioles, and capillaries. The pulmonary arteries are thinner (one-third the thickness of their counterpart systemic vessels) and have a larger diameter. The combined effect makes them much more distensible and compliant (approximately 7mL/mmHg).
The venous circuit begins with the venules that drain the capillaries. They join to form smaller veins and eventually merge to form the main pulmonary veins draining into the left atrium. Like the arteries, the pulmonary veins are thinner and more distensible than the counterpart systemic veins and accommodate more blood because of their larger compliance.
Lymphatics play a crucial role in maintaining a dry alveolar membrane and preventing accumulation of tissue fluid around the pulmonary circulation. They can be found close to the terminal bronchioles and drain the mediastinal lymphatics before emptying into the right lymphatic duct.

Title: Physiology, Pulmonary Ventilation and Perfusion

Authors: Powers KA, Dhamoon AS.

Journal: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

Link to PubMed: Physiology, Pulmonary Ventilation and Perfusion

Abstract: One of the major roles of the lungs is to facilitate gas exchange between the circulatory system and the external environment. The lungs are composed of branching airways that terminate in respiratory bronchioles and alveoli, which participate in gas exchange. Most bronchioles and large airways are part of the conducting zone of the lung, which delivers gas to sites of gas exchange in alveoli. Gas exchange occurs in the lungs between alveolar air and the blood of the pulmonary capillaries. For effective gas exchange to occur, alveoli must be ventilated and perfused. Ventilation (V) refers to the flow of air into and out of the alveoli, while perfusion (Q) refers to the flow of blood to alveolar capillaries. Individual alveoli have variable degrees of ventilation and perfusion in different regions of the lungs. Collective changes in ventilation and perfusion in the lungs are measured clinically using the ratio of ventilation to perfusion (V/Q). Changes in the V/Q ratio can affect gas exchange and can contribute to hypoxemia.

Title: Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes

Authors: Mebrate Y, Willson K, Manisty CH, Baruah R, Mayet J, Hughes AD, Parker KH, Francis DP.

Journal: J Appl Physiol (1985). 2009 Sep;107(3):696-706. doi: 10.1152/japplphysiol.90308.2008. Epub 2009 Jul 23. PMID: 19628721; PMCID: PMC2755997.

Link to full text: Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes

Abstract: We examine the potential to treat unstable ventilatory control (seen in periodic breathing, Cheyne-Stokes respiration, and central sleep apnea) with carefully controlled dynamic administration of supplementary CO(2), aiming to reduce ventilatory oscillations with minimum increment in mean CO(2). We used a standard mathematical model to explore the consequences of phasic CO(2) administration, with different timing and dosing algorithms. We found an optimal time window within the ventilation cycle (covering approximately 1/6 of the cycle) during which CO(2) delivery reduces ventilatory fluctuations by >95%. Outside that time, therapy is dramatically less effective: indeed, for more than two-thirds of the cycle, therapy increases ventilatory fluctuations >30%. Efficiency of stabilizing ventilation improved when the algorithm gave a graded increase in CO(2) dose (by controlling its duration or concentration) for more severe periodic breathing. Combining gradations of duration and concentration further increased efficiency of therapy by 22%. The (undesirable) increment in mean end-tidal CO(2) caused was 300 times smaller with dynamic therapy than with static therapy, to achieve the same degree of ventilatory stabilization (0.0005 vs. 0.1710 kPa). The increase in average ventilation was also much smaller with dynamic than static therapy (0.005 vs. 2.015 l/min). We conclude that, if administered dynamically, dramatically smaller quantities of CO(2) could be used to reduce periodic breathing, with minimal adverse effects. Algorithms adjusting both duration and concentration in real time would achieve this most efficiently. If developed clinically as a therapy for periodic breathing, this would minimize excess acidosis, hyperventilation, and sympathetic overactivation, compared with static treatment.

Title: The effects of carbon dioxide in champagne on psychometric performance and blood-alcohol concentration

Authors: Ridout F, Gould S, Nunes C, Hindmarch I.

Journal: Alcohol Alcohol. 2003 Jul-Aug;38(4):381-5. doi: 10.1093/alcalc/agg092. PMID: 12814909.

Link to PubMed: The effects of carbon dioxide in champagne on psychometric performance and blood-alcohol concentration

Abstract: Aims: To assess the effects of carbon dioxide (CO(2)) in champagne on psychomotor performance and blood-alcohol concentration (BAC).

Methods: Twelve subjects consumed ethanol (0.6 g/kg body weight) served as champagne or champagne with the CO(2) removed, in a crossover study.

Results: Champagne produced significantly greater BACs and significantly increased reaction times in a divided attention task, than degassed champagne.

Conclusions: The CO(2) in champagne may accelerate absorption of alcohol, leading to more rapid or severe intoxication.

Title: Alcohol concentration and carbonation of drinks: the effect on blood alcohol levels

Authors: Roberts C, Robinson SP.

Journal: J Forensic Leg Med. 2007 Oct;14(7):398-405. doi: 10.1016/j.jflm.2006.12.010. Epub 2007 May 16. PMID: 17720590.

Link to PubMed: Alcohol concentration and carbonation of drinks: the effect on blood alcohol levels

Abstract: Alcohol absorption and elimination vary considerably amongst individuals, and are subject to influences from a variety of factors. The effects of alcohol concentration and beverage mixer type on the rate of alcohol absorption, in a controlled environment was studied. 21 subjects (12 male, 9 female) consumed a solution containing alcohol, on three separate occasions. The three solutions were, A: Neat vodka (37.5 vol%), B: Vodka mixed with still water (18.75 vol%), C: Vodka mixed with carbonated water (18.75 vol%). The volume of alcohol each subject consumed was determined by Widmark's equation. The alcohol was drunk in a 5 min period following an overnight fast and breath alcohol concentrations were measured over a 4h period using a breathalyser. 20/21 subjects absorbed the dilute alcohol at a faster rate than the concentrated alcohol. The difference between the absorption rates was found to be significant (p<0.001). The use of a carbonated mixer had varying effects on the alcohol absorption rate. 14/21 subjects absorbed the alcohol with the carbonated mixer at a faster rate, with 7 subjects showing either no change or a decrease in rate. The mean absorption rate for solution C was 4.39+/-0.45 (mg/100ml/min), and the difference between this absorption rate and that with the still mixer (1.08+0.36) was significant (p=0.006).

Title: Intraoperative End-Tidal Carbon Dioxide Concentrations: What Is the Target?

Authors: Way M, Hill GE.

Journal: Anesthesiol Res Pract. 2011;2011:271539. doi: 10.1155/2011/271539. Epub 2011 Oct 25. PMID: 22110496; PMCID: PMC3202118.

Link to full text: Intraoperative End-Tidal Carbon Dioxide Concentrations: What Is the Target?

Abstract: Recent publications suggest that target end-tidal carbon dioxide concentrations should be higher than values currently considered as acceptable. This paper presents evidence that end-tidal carbon dioxide values higher than concentrations that are currently targeted result in improved patient outcomes and are associated with a reduced incidence of postoperative complications.

Title: Association between Mouth Breathing and Atopic Dermatitis in Japanese Children 2-6 years Old: A Population-Based Cross-Sectional Study

Authors: Yamaguchi H, Tada S, Nakanishi Y, Kawaminami S, Shin T, Tabata R, Yuasa S, Shimizu N, Kohno M, Tsuchiya A, Tani K.

Journal: PLoS One. 2015 Apr 27;10(4):e0125916. doi: 10.1371/journal.pone.0125916. PMID: 25915864; PMCID: PMC4411141.

Link to full text: Association between Mouth Breathing and Atopic Dermatitis in Japanese Children 2-6 years Old: A Population-Based Cross-Sectional Study

Abstract: As mouth breathing is associated with asthma and otitis media, it may be associated with other diseases. Therefore, this population-based cross-sectional study evaluated the association of mouth breathing with the prevalences of various diseases in children. Preschool children older than 2 years were included. A questionnaire was given to parents/guardians at 13 nurseries in Tokushima City. There were 468 valid responses (45.2%). We defined a subject as a mouth breather in daytime (MBD) if they had 2 or more positive items among the 3 following items: "breathes with mouth ordinarily," "mouth is open ordinarily," and "mouth is open when chewing." We defined subjects as mouth breathers during sleep (MBS) if they had 2 or more positive items among the following 3 items: "snoring," "mouth is open during sleeping," and "mouth is dry when your child gets up." The prevalences of MBD and MBS were 35.5% and 45.9%, respectively. There were significant associations between MBD and atopic dermatitis (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.4-4.2), MBS and atopic dermatitis (OR: 2.4, 95% CI: 1.3-4.2), and MBD and asthma (OR: 2.2, 95% CI: 1.2-4.0). After adjusting for history of asthma and allergic rhinitis; family history of atopic dermatitis, asthma, and allergic rhinitis; and nasal congestion; both MBD (OR: 2.6, 95% CI: 1.3-5.4) and MBS (OR: 4.1, 95% CI: 1.8-9.2) were significantly associated with atopic dermatitis. In preschool children older than 2 years, both MBD and MBS may be associated with the onset or development of atopic dermatitis.

Title: Carbon dioxide homeostasis and recovery after general anaesthesia

Authors: Hovorka J.

Journal: Acta Anaesthesiol Scand. 1982 Oct;26(5):498-504. doi: 10.1111/j.1399-6576.1982.tb01806.x. PMID: 6815976.

Link to PubMed: Carbon dioxide homeostasis and recovery after general anaesthesia

Abstract: The influence of different levels of carbon dioxide during general anaesthesia on postoperative recovery was studied. Sixty female patients were divided into two age groups. Thirty patients were over 60 years old and 30 patients were under 46 years old. Artificial ventilation with added carbon dioxide during general anaesthesia with thiopentone, nitrous oxide-oxygen, alcuronium and fentanyl was used. According to the arterial CO2 tension, patients were allocated to subgroups: hypercarbic, PaCO2 7.3 kPa, normocarbic, PaCO2 5.3 kPa and two different levels of hypocarbia: older patients PaCO2 3.7 kPa and younger patients PaCO2 2.9 kPa. As criteria for recovery, a battery of recovery tests and postoperative questionnaires were used. Regardless of age, patients subjected to hypercarbic ventilation scored better in the recovery tests than patients subjected to normo- or hypocarbia. Normocarbic ventilation also gave better results than hypocarbic ventilation. The level of hypocarbia used in the older patients and that used in the younger patients, though different, resulted in nearly the same deterioration of scoring in the recovery tests. This deterioration was seen in some patients up to 48 h postoperatively. No subjective differences were elicited from the questionnaires after various types of ventilation.

Title: Carbon dioxide tolerability and toxicity in rat and man: A translational study

Authors: van der Schrier R, van Velzen M, Roozekrans M, Sarton E, Olofsen E, Niesters M, Smulders C, Dahan A.

Journal: Front Toxicol. 2022 Oct 13;4:1001709. doi: 10.3389/ftox.2022.1001709. PMID: 36310693; PMCID: PMC9606673.

Link to full text: Carbon dioxide tolerability and toxicity in rat and man: A translational study

Abstract: Background: Due the increasing need for storage of carbon dioxide (CO2) more individuals are prone to be exposed to high concentrations of CO2 accidentally released into atmosphere, with deleterious consequences. Methods: We tested the effect of increasing CO2 concentrations in humans (6-12%) and rats (10-50%) at varying inhalation times (10-60 min). In humans, a continuous positive airway pressure helmet was used to deliver the gas mixture to the participants. Unrestrained rats were exposed to CO2 in a transparent chamber. In both species regular arterial blood gas samples were obtained. After the studies, the lungs of the animals were examined for macroscopic and microscopic abnormalities. Results: In humans, CO2 concentrations of 9% inhaled for >10 min, and higher concentrations inhaled for <10 min were poorly or not tolerated due to exhaustion, anxiety, dissociation or acidosis (pH < 7.2), despite intact oxygenation. In rats, concentrations of 30% and higher were associated with CO2 narcosis, epilepsy, poor oxygenation and, at 50% CO2, spontaneous death. Lung hemorrhage and edema were observed in the rats at inhaled concentrations of 30% and higher. Conclusion: This study provides essential insight into the occurrence of physiological changes in humans and fatalities in rats after acute exposure to high levels of CO2. Humans tolerate 9% CO2 and retain their ability to function coherently for up to 10 min. These data support reconsideration of the current CO2 levels (<7.5%) that pose a risk to exposed individuals (<7.5%) as determined by governmental agencies to ≤9%.

Keywords: CO2 storage; CO2 transport; carbon dioxide; tolerability; toxicity; translational study.

Title: Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies

Authors: Meuret AE, Ritz T.

Journal: Int J Psychophysiol. 2010 Oct;78(1):68-79. doi: 10.1016/j.ijpsycho.2010.05.006. Epub 2010 May 25. PMID: 20685222; PMCID: PMC2937087.

Link to full text: Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies

Abstract: Sustained or spontaneous hyperventilation has been associated with a variety of physical symptoms and has been linked to a number of organic illnesses and mental disorders. Theories of panic disorder hold that hyperventilation either produces feared symptoms of hypocapnia or protects against feared suffocation symptoms of hypercapnia. Although the evidence for both theories is inconclusive, findings from observational, experimental, and therapeutic studies suggest an important role of low carbon dioxide (CO2) levels in this disorder. Similarly, hypocapnia and associated hyperpnia are linked to bronchoconstriction, symptom exacerbation, and lower quality of life in patients with asthma. Raising CO2 levels by means of therapeutic capnometry has proven beneficial effects in both disorders, and the reversing of hyperventilation has emerged as a potent mediator for reductions in panic symptom severity and treatment success.

Title: Association of lung function with overall mortality is independent of inflammatory, cardiac, and functional biomarkers in older adults: the ActiFE-study

Authors: Weinmayr, G., Schulz, H., Klenk, J., Denkinger, M., Duran-Tauleria, E., Koenig, W., ... & ActiFE Study Group Böhm B. 12 13 Geiger H. 14 Laszlo R. 15 Steinacker JM 15 Ludolph A. 16 von Arnim C. 16 Lukas A. 17 Peter R. 18 Rapp K. 4 Riepe M. 19 Scharffetter-Kochanek K. 20 Stingl J. 21.

Journal: Scientific reports 10.1 (2020): 11862.

Link to full text: Association of lung function with overall mortality is independent of inflammatory, cardiac, and functional biomarkers in older adults: the ActiFE-study

Abstract: Reduced lung function is associated with overall and cardiovascular mortality. Chronic low grade systemic inflammation is linked to impaired lung function and cardiovascular outcomes.We assessed the association of lung function with overall 8-year mortality in 867 individuals of theActivity and Function in the Elderly study using confounder-adjusted Cox proportional hazards models (including gait speed and daily walking time as measures of physical function) without and with adjustment for inflammatory and cardiac markers. Forced expiratory volume in 1 s/forced vital capacity ­(FEV1/FVC) but not FVC was related to mortality after adjustment for physical function and other confounders. Additional adjustment for inflammatory and cardiac markers did not change the hazard ratios (HR) markedly, e.g. for a ­FEV1/FVC below 0.7 from 1.55 [95% confdence-interval (CI) 1.14–2.11] to 1.49 (95% CI 1.09–2.03).These independent associations were also observed in the apparently lung healthy subpopulation with even higher HRs up to 2.76 (95% CI 1.52–4.93).A measure of airfow limitation but not vital capacity was associated with overall mortality in this community-dwelling older population and in the subgroup classifed as lung healthy.These associations were independent of adjustment for inflammatory and cardiac markers and support the role of airfow limitation as independent predictor of mortality in older adults.

Title: The effect of pursed lips breathing in increasing oxygen saturation in patients with chronic obstructive pulmonary disease in internal ward 2 of the general hospital of dr. R. Soedarsono pasuruan

Authors: Budiono, B., Mustayah, M., & Aindrianingsih, A.

Journal: Public Health of Indonesia 3.3 (2017): 117-123.

Link to full text: The effect of pursed lips breathing in increasing oxygen saturation in patients with chronic obstructive pulmonary disease in internal ward 2 of the general hospital of dr. R. Soedarsono pasuruan

Abstract: Background: Chronic obstructive pulmonary disease is a leading cause of death and disability. Thus, the effort to reduce the symptoms, such as dyspnea is necessity. Pursed lip breathing is assumed increasing oxygen saturation.
Objective: This study aims to determine the effect of pursed lips breathing in increasing oxygen saturation in patients with COPD in internal ward 2 of the General Hospital of Dr. R. Soedarsono Pasuruan on May 16 - June 30, 2017.
Methods: This was a pre-experimental design with pre-posttest design. There were 24 patients with COPD selected using simple random sampling technique. Pulse oximetry (oximeter pulse fingertip) was used to measure oxygen saturation. Data were analyzed using Wilcoxon Sign Rank Test.
Results: Findings showed p-value 0.000 (<0.05), which indicated that there was a statistically significant difference in oxygen saturation before and after pursed lips breathing.
Conclusion: There was a significant effect of pursed lips breathing on oxygen saturation in patients with COPD in the internal ward 2 of the general hospital of Dr. R. Soedarsono Pasuruan. Thus, pursed lips breathing could be applied as a nursing intervention in patients with COPD.
Key words: Pursed lips breathing, COPD, oxygen saturation

Title: A comparison between the airway response to isocapnic hyperventilation and hypertonic saline in subjects with asthma

Authors: Smith CM, Anderson SD.

Journal: Eur Respir J. 1989 Jan;2(1):36-43. PMID: 2495982.

Link to PubMed: A comparison between the airway response to isocapnic hyperventilation and hypertonic saline in subjects with asthma

Abstract: We compared the response to isocapnic hyperventilation (ISH), where both cooling and drying of the mucosa occur, with the response to inhaling aerosols of hypertonic saline (HS), where airway osmolarity increases without airway cooling. We studied nine subjects on two days. For ISH, subjects ventilated at 70% of their estimated maximum voluntary ventilation (MVV). For HS, they inhaled aerosols of 2.7, 3.6, or 4.5% saline. The concentration that was used depended on the rate of ventilation during ISH. For both challenges the stimulus was given for one minute. Forced expiratory volume in one second (FEV1) was measured once between each minute, and the challenge ceased when the FEV1 did not change for two successive minutes. A plateau in FEV1 occurred after 8.1 +/- 2.4 (mean +/- 1 SD) min of ISH, and 8.3 +/- 2.4 min of HS. The lowest FEV1 (% predicted) after ISH was 45 +/- 16% and after HS was 51 +/- 18% (r = 0.93). However, the maximum responses occurred after the final challenge and were not the same as the plateau. For HS, the plateau represented 89 +/- 11% of the maximum response which developed within one minute of the final challenge. For ISH, the plateau was only 56 +/- 26% of the maximum response, which developed within 5.2 +/- 2.9 min after challenge. The similarities in the response to these challenges are consistent with the hypothesis that ISH induces asthma via hyperosmolarity. The delayed response to ISH suggests that cooling may delay the response to hyperosmolarity.

Title: Respiratory Abnormalities in Parkinson's Disease: What Do We Know from Studies in Humans and Animal Models?

Authors: Kaczyńska K, Orłowska ME, Andrzejewski K.

Journal: Int J Mol Sci. 2022 Mar 23;23(7):3499. doi: 10.3390/ijms23073499. PMID: 35408858; PMCID: PMC8998219.

Link to full text: Respiratory Abnormalities in Parkinson's Disease: What Do We Know from Studies in Humans and Animal Models?

Abstract: Parkinson's disease (PD) is the second most common progressive neurodegenerative disease characterized by movement disorders due to the progressive loss of dopaminergic neurons in the ventrolateral region of the substantia nigra pars compacta (SNpc). Apart from the cardinal motor symptoms such as rigidity and bradykinesia, non-motor symptoms including those associated with respiratory dysfunction are of increasing interest. Not only can they impair the patients' quality of life but they also can cause aspiration pneumonia, which is the leading cause of death among PD patients. This narrative review attempts to summarize the existing literature on respiratory impairments reported in human studies, as well as what is newly known from studies in animal models of the disease. Discussed are not only respiratory muscle dysfunction, apnea, and dyspnea, but also altered central respiratory control, responses to hypercapnia and hypoxia, and how they are affected by the pharmacological treatment of PD.

Keywords: Parkinson's disease; apnea; dyspnea; hypercapnia; hypoxia; respiratory dysfunction.

Title: Respiratory alkalosis in children with febrile seizures

Authors: Schuchmann S, Hauck S, Henning S, Grüters-Kieslich A, Vanhatalo S, Schmitz D, Kaila K.

Journal: Epilepsia. 2011 Nov;52(11):1949-55. doi: 10.1111/j.1528-1167.2011.03259.x. Epub 2011 Sep 12. PMID: 21910730.

Link to full text: Respiratory alkalosis in children with febrile seizures

Abstract: Purpose: Febrile seizures (FS) are the most common type of convulsive events in children. FS are suggested to result from a combination of genetic and environmental factors. However, the pathophysiologic mechanisms underlying FS remain unclear. Using an animal model of experimental FS, it was demonstrated that hyperthermia causes respiratory alkalosis with consequent brain alkalosis and seizures. Here we examine the acid-base status of children who were admitted to the hospital for FS. Children who were admitted because of gastroenteritis (GE), a condition known to promote acidosis, were examined to investigate a possible protective effect of acidosis against FS.

Methods: We enrolled 433 age-matched children with similar levels of fever from two groups presented to the emergency department. One group was admitted for FS (n = 213) and the other for GE (n = 220). In the FS group, the etiology of fever was respiratory tract infection (74.2%), otitis media (7%), GE (7%), tonsillitis (4.2%), scarlet fever (2.3%) chickenpox (1.4%), urinary tract infection (1.4%), postvaccination reaction (0.9%), or unidentified (1.4%). In all patients, capillary pH and blood Pco(2) were measured immediately on admission to the hospital.

Key findings: Respiratory alkalosis was found in children with FS (pH 7.46 ± 0.04, [mean ± standard deviation] Pco(2) 29.5 ± 5.5 mmHg), whereas a metabolic acidosis was seen in all children admitted for GE (pH 7.31 ± 0.03, Pco(2) 37.7 ± 4.3 mmHg; p < 0.001 for both parameters). No FS were observed in the latter group. A subgroup (n = 15; 7%) of the patients with FS had GE and, notably, their blood pH was more alkaline (pH 7.44 ± 0.04) than in the GE-admitted group. During the enrollment period, eight of the patients were admitted on separate occasions because of FS or GE. Consistent with the view that generation of FS requires a genetic susceptibility in addition to acute seizure triggering factors, each of these patients had an alkalotic blood pH when admitted because of FS, whereas they had an acidotic pH (and no FS) when admitted because of GE (pH 7.47 ± 0.05 vs. pH 7.33 ± 0.03, p < 0.005).

Significance: The results show that FS are associated with a systemic respiratory alkalosis, irrespective of the severity of the underlying infection as indicated by the level of fever. The lack of FS in GE patients is attributable to low pH, which also explains the fact that children with a susceptibility to FS do not have seizures when they have GE-induced fever that is associated with acidosis. The present demonstration of a close link between FS and respiratory alkalosis may pave the way for further clinical studies and attempts to design novel therapies for the treatment of FS by controlling the systemic acid-base status.

Title: Respiratory Dysfunction in Alzheimer's Disease-Consequence or Underlying Cause? Applying Animal Models to the Study of Respiratory Malfunctions

Authors: Wrzesień A, Andrzejewski K, Jampolska M, Kaczyńska K.

Journal: Int J Mol Sci. 2024 Feb 16;25(4):2327. doi: 10.3390/ijms25042327. PMID: 38397004; PMCID: PMC10888758.

Link to full text: Respiratory Dysfunction in Alzheimer's Disease-Consequence or Underlying Cause? Applying Animal Models to the Study of Respiratory Malfunctions

Abstract: Alzheimer's disease (AD) is a neurodegenerative brain disease that is the most common cause of dementia among the elderly. In addition to dementia, which is the loss of cognitive function, including thinking, remembering, and reasoning, and behavioral abilities, AD patients also experience respiratory disturbances. The most common respiratory problems observed in AD patients are pneumonia, shortness of breath, respiratory muscle weakness, and obstructive sleep apnea (OSA). The latter is considered an outcome of Alzheimer's disease and is suggested to be a causative factor. While this narrative review addresses the bidirectional relationship between obstructive sleep apnea and Alzheimer's disease and reports on existing studies describing the most common respiratory disorders found in patients with Alzheimer's disease, its main purpose is to review all currently available studies using animal models of Alzheimer's disease to study respiratory impairments. These studies on animal models of AD are few in number but are crucial for establishing mechanisms, causation, implementing potential therapies for respiratory disorders, and ultimately applying these findings to clinical practice. This review summarizes what is already known in the context of research on respiratory disorders in animal models, while pointing out directions for future research.

Keywords: Alzheimer's disease; animal models; hypercapnia; hypoxia; respiratory disorders; sleep obstructive apnea.

Title: Respiratory dysfunction in Parkinson's disease: a narrative review

Authors: D'Arrigo A, Floro S, Bartesaghi F, Casellato C, Sferrazza Papa GF, Centanni S, Priori A, Bocci T.

Journal: ERJ Open Res. 2020 Oct 5;6(4):00165-2020. doi: 10.1183/23120541.00165-2020. PMID: 33043046; PMCID: PMC7533305.

Link to full text: Respiratory dysfunction in Parkinson's disease: a narrative review

Abstract: The presence of respiratory symptoms in Parkinson's disease (PD) has been known since the first description of the disease, even though the prevalence and incidence of these disturbances are not well defined. Several causes have been reported, comprising obstructive and restrictive pulmonary disease and changes in the central ventilatory control, and different pathogenetic mechanisms have been postulated accordingly. In our review, we encompass the current knowledge about respiratory abnormalities in PD, as well as the impact of anti-Parkinsonian drugs as either risk or protective factors. A description of putative pathogenetic mechanisms is also provided, and possible treatments are discussed, focusing on the importance of recognising and treating respiratory symptoms as a key manifestation of the disease itself. A brief description of respiratory dysfunctions in atypical Parkinsonism, especially α-synucleinopathies, is also provided.

Title: Acetazolamide: a second wind for a respiratory stimulant in the intensive care unit?

Authors: Heming N, Urien S, Faisy C.

Journal: Crit Care. 2012 Aug 7;16(4):318. doi: 10.1186/cc11323. PMID: 22866939; PMCID: PMC3580678.

Link to full text: Acetazolamide: a second wind for a respiratory stimulant in the intensive care unit?

Abstract: Patients with chronic obstructive pulmonary disease (COPD) are affected by episodes of respiratory exacerbations, some of which can be severe and may necessitate respiratory support. Prolonged invasive mechanical ventilation is associated with increased mortality rates. Persistent failure to discontinue invasive mechanical ventilation is a major issue in patients with COPD. Pure or mixed metabolic alkalosis is a common finding in the intensive care unit (ICU) and is associated with a worse outcome. In patients with COPD, the condition is called post-hypercapnic alkalosis and is a complication of mechanical ventilation. Reversal of metabolic alkalosis may facilitate weaning from mechanical ventilation of patients with COPD. Acetazolamide, a non-specific carbonic anhydrase inhibitor, is one of the drugs employed in the ICU to reverse metabolic alkalosis. The drug is relatively safe, undesirable effects being rare. The compartmentalization of the different isoforms of the carbonic anhydrase enzyme may, in part, explain the lack of evidence of the efficacy of acetazolamide as a respiratory stimulant. Recent findings suggest that the usually employed doses of acetazolamide in the ICU may be insufficient to significantly improve respiratory parameters in mechanically ventilated patients with COPD. Randomized controlled trials using adequate doses of acetazolamide are required to address this issue.

Title: Carbon dioxide in the critically ill: too much or too little of a good thing?

Authors: Marhong J, Fan E.

Journal: Respir Care. 2014 Oct;59(10):1597-605. doi: 10.4187/respcare.03405. PMID: 25261559.

Link to full text: Carbon dioxide in the critically ill: too much or too little of a good thing?

Abstract: Hypercapnia and hypocapnia commonly complicate conditions that are present in critically ill patients. Both conditions have important physiologic effects that may impact the clinical management of these patients. For instance, hypercapnia results in bronchodilation and enhanced hypoxic vasoconstriction, leading to improved ventilation/perfusion matching. Hypocapnia reduces cerebral blood volume through arterial vasoconstriction. These effects have also been exploited for therapeutic aims. In patients with traumatic brain injury (TBI), hypocapnia is often utilized to control intracranial pressure. However, this effect is not sustained, and prolonged hypocapnia increases the risk of mortality and severe disability in patients with TBI. Hypercapnia and hypercapnic acidosis are common consequences of lung-protective ventilation in ARDS. Hypercapnic acidosis reduces ischemic lung injury and preserves lung compliance, but concern has arisen over hypercapnia-induced immunosuppression and the potential for bacterial proliferation in sepsis. Experimental studies suggest that buffering hypercapnic acidosis attenuates these effects, whereas hypocapnia appears to potentiate lung injury through increased capillary permeability and decreased lung compliance. Several areas of uncertainty surround the role of hypercapnia/hypocapnia in treating TBI and ARDS. Current data support recommendations to avoid hypocapnia in treating TBI, with the exception of emergent treatment of elevated intracranial pressure, while awaiting definitive management. Permissive hypercapnia is commonly accepted as a consequence of lung-protective ventilation in ARDS, but there is insufficient evidence to support the induction of hypercapnic acidosis in clinical practice. Buffering hypercapnic acidosis should be considered only for a specific clinical indication (eg, hemodynamic instability). For clinicians choosing to buffer hypercapnic acidosis, tris-hydroxymethyl aminomethane is recommended over sodium bicarbonate, as it is more effective in correcting pH and is not associated with increased carbon dioxide production. Future studies should aim to address these areas of uncertainty to help guide clinicians in the therapeutic use and management of hypercapnia/hypocapnia in critically ill patients.

Keywords: hypercapnia; hypocapnia; intensive care units; respiration, artificial; respiratory acidosis; respiratory distress syndrome, adult.

Title: Gaseous nitric oxide failed to inhibit the replication cycle of SARS-CoV-2 in vitro

Authors: Rousseaud A, Prot M, Loriere ES, Katz I, Ramirez-Gil JF, Farjot G.

Journal: Nitric Oxide. 2023 Mar 1;132:27-33. doi: 10.1016/j.niox.2023.01.004. Epub 2023 Jan 25. PMID: 36706864; PMCID: PMC9873364.

Link to full text: Gaseous nitric oxide failed to inhibit the replication cycle of SARS-CoV-2 in vitro

Abstract: Nitric oxide (NO) has been shown to have antimicrobial activity in vitro and in some in vivo models, while the virucidal activity of NO remains elusive. Some studies using NO donors have suggested that NO could be a potential candidate to treat SARS-CoV infection. The Covid-19 pandemic raised the hypothesis that NO gas might have an impact on Sars-CoV-2 replication cycle and might be considered as a candidate therapy to treat COVID-19. To our knowledge, there are no in vitro preclinical studies demonstrating a virucidal effect of gaseous NO on SARS-CoV-2. This study aims to determine whether gaseous NO has an impact on the replication cycle of SARS-CoV-2 in vitro. To that end, SARS-CoV-2 infected epithelial (VeroE6) and pulmonary (A549-hACE2) cells were treated with repeated doses of gaseous NO at different concentrations known to be efficient against bacteria. Our results show that exposing SARS-CoV-2 infected-cells to NO gas even at high doses (160 ppm, 6 h) does not influence the replication cycle of the virus in vitro. We report here that NO gas has no antiviral properties in vitro on SARS-COV-2. Therefore, there is no rationale for its usage in clinical settings to treat COVID-19 patients for direct antiviral purposes, which does not exclude other potential physiological benefits of this gas.

Keywords: COVID-19; Gaseous nitric oxide; SARS-CoV-2.

Title: Oxidative Stress in the Lung - The Essential Paradox

Authors: Rogers LK, Cismowski MJ.

Journal: Curr Opin Toxicol. 2018 Feb;7:37-43. doi: 10.1016/j.cotox.2017.09.001. Epub 2017 Sep 19. PMID: 29308441; PMCID: PMC5754020.

Link to full text: Oxidative Stress in the Lung - The Essential Paradox

Abstract: As eukaryotic life evolved, so too did the need for a source of energy that meets the requirements of complex organisms. Oxygen provides this vast potential energy source, but the same chemical reactivity which provides this potential also can have detrimental effects. The lung evolved as an organ that can efficiently promote gas exchange for the entire organism but as such, the lung is highly susceptible to its external environment. Oxygen can be transformed through both enzymatic and non-enzymatic processes into reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can lead to protein, lipid, and DNA damage. Under normal conditions ROS/RNS concentrations are minimized through the activity of antioxidants located both intracellularly and in the epithelial lining fluid of the lung. Oxidative stress in the lung results when the antioxidant capacity is overwhelmed or depleted through external exposures, such as altered oxygen tension or air pollution, or internally. Internal sources of oxidative stress include systemic disease and the activation of resident cells and inflammatory cells recruited in response to an exposure or systemic response. Pulmonary responses to oxidative stress include activation of oxidases, lipid peroxidation, increases in nitric oxide, and autophagy. These internal and external exposures with the subsequent pulmonary responses contribute to development of diseases directly linked to oxidative stress. These include asthma, COPD, and lung cancers. While the vulnerability of the lung to oxidative stress is acknowledged, few effective preventative strategies or therapeutics are currently available.