COVID-19 patients often experience dyspnea due to several factors. The underlying unique pathophysiology of dyspnea in COVID-19 is not yet fully understood, but it is believed to be related to a combination of respiratory, cardiovascular, and neuromuscular factors. Hypoxemia is considered one of the key symptoms of COVID-19. This affects the respiratory drive, which determines the rate, depth, and pattern of breathing. The relationship between increased ventilatory neural drive and abnormal gas exchange, particularly in the context of ventilation/perfusion (V/Q) mismatches and chemosensitivity, has gained significant attention following the COVID-19 pandemic. The ACE2 receptors allow viral entry into the lungs, leading to the loss of surfactant, hypoxic vasoconstriction, and intrapulmonary shunting that may result in a V/Q mismatch. Additionally, acidosis, hypercapnia, elevated 2,3-diphosphogly-cerate levels and fever may shift the oxygen diffusion curve rightward, lowering arterial oxygen saturation levels and triggering ventilatory responses. This paper examines how physio pathological factors such as altered gas diffusion, chemosensory feedback, V/Q ratios, altered compliance, arterial blood gases, and respiratory muscle dysfunction in these patients affect ventilatory drive. A review of the published literature was also conducted to determine the mechanism of dyspnea. To ensure appropriate gas exchange, individuals need to augment their minute ventilation (VE) when physiological dead space is elevated. This serves as a compensatory mechanism to counteract the effects of compromised gas exchange and keep adequate oxygenation throughout the body. The respiratory centers may experience dysregulation due to the impact of the virus on the respiratory system, which could affect the rhythm-generating and pattern-generating signals that are vital for regulating the respiratory rate and depth of breathing effort. The cerebral cortex, in conjunction with the brain stem centers, plays a crucial role in regulating ventilation during prolonged hypoxemia. This interaction between these two components may help elucidate the conscious respiratory sensation (or dyspnea) experienced by patients. It is hypothesized that neuroventilatory decoupling acts as a mechanism to prevent sensory signals from translating into mechanical or ventilatory responses. This decoupling phenomenon is believed to have a notable impact on the intensity of breathlessness. By understanding the relationship between increased ventilatory neural drive and abnormal gas exchange, particularly in
References
[1]
Vaporidi, K., Akoumianaki, E., Telias, I., Goligher, E.C., Brochard, L. and Georgopoulos, D. (2020) Respiratory Drive in Critically Ill Patients. Pathophysiology and Clinical Implications.American Journal of Respiratory and Critical Care Medicine, 201, 20-32. https://doi.org/10.1164/rccm.201903-0596SO
[2]
Esnault, P., Cardinale, M., Hraiech, S., Goutorbe, P., Baumstrack, K., Prud’homme, E., Bordes, J., Forel, J.-M., Meaudre, E., Papazian, L. and Guervilly, C. (2020) High Respiratory Drive and Excessive Respiratory Efforts Predict Relapse of Respiratory Failure in Critically Ill Patients with COVID-19. American Journal of Respiratory and Critical Care Medicine, 202, 1173-1178. https://doi.org/10.1164/rccm.202005-1582LE
[3]
Yong, S.J. (2021) Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chemical Neuroscience, 12, 573-580. https://doi.org/10.1021/acschemneuro.0c00793
[4]
Fara, A., Mitrev, Z., Rosalia, R.A. and Assas, B.M. (2020) Cytokine Storm and COVID-19: A Chronicle of Pro-Inflammatory Cytokines. Open Biology, 10, Article ID: 200160. https://doi.org/10.1098/rsob.200160
[5]
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M. and Cao, B. (2020) Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. The Lancet, 395, 497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
[6]
Guan, W., Ni, Z., Hu, Y., Liang, W., Ou, C., He, J., Liu, L., Shan, H., Lei, C., Hui, D. S.C., Du, B., Li, L., Zeng, G., Yuen, K.-Y., Chen, R., Tang, C., Wang, T., Chen, P., Xiang, J. and Zhong, N. (2020) Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine, 382, 1708-1720. https://doi.org/10.1056/NEJMoa2002032
[7]
Xie, J., Tong, Z., Guan, X., Du, B., Qiu, H. and Slutsky, A.S. (2020) Critical Care Crisis and Some Recommendations during the COVID-19 Epidemic in China. Intensive Care Medicine, 46, 837-840. https://doi.org/10.1007/s00134-020-05979-7
[8]
Tobin, M.J., Laghi, F. and Jubran, A. (2020) Caution about Early Intubation and Mechanical Ventilation in COVID-19. Annals of Intensive Care, 10, Article No. 78. https://doi.org/10.1186/s13613-020-00692-6
[9]
Archer, S.L., Sharp, W.W. and Weir, E.K. (2020) Differentiating COVID-19 Pneumonia from Acute Respiratory Distress Syndrome and High Altitude Pulmonary Edema: Therapeutic Implications. Circulation, 142, 101-104. https://doi.org/10.1161/CIRCULATIONAHA.120.047915
[10]
Ottestad, W. and Søvik, S. (2020) COVID-19 Patients with Respiratory Failure: What Can We Learn from Aviation Medicine? British Journal of Anaesthesia, 125, e280-e281. https://doi.org/10.1016/j.bja.2020.04.012
[11]
Toy, S. and Roland, D. (2020) Some Doctors Pull Back on Using Ventilators to Treat Covid-19. Wall Street Journal. https://www.wsj.com/articles/some-doctors-pull-back-on-using-ventilators-to-treat-covid-19-11589103001
[12]
Fisher, H. K. (2020) Hypoxemia in COVID-19 Patients: An Hypothesis. Medical Hypotheses, 143, Article ID: 110022. https://doi.org/10.1016/j.mehy.2020.110022
[13]
Shenoy, N., Luchtel, R. and Gulani, P. (2020) Considerations for Target Oxygen Saturation in COVID-19 Patients: Are We Under-Shooting? BMC Medicine, 18, Article No. 260. https://doi.org/10.1186/s12916-020-01735-2
[14]
Moammar, M.Q., Azam, H.M., Blamoun, A.I., Rashid, A.O., Ismail, M., Khan, M.A. and DeBari, V.A. (2008) Alveolar-Arterial Oxygen Gradient, Pneumonia Severity Index and Outcomes in Patients Hospitalized with Community Acquired Pneumonia. Clinical and Experimental Pharmacology and Physiology, 35, 1032-1037. https://doi.org/10.1111/j.1440-1681.2008.04971.x
[15]
Yuan, S., Jiang, S.-C., Zhang, Z.-W., Fu, Y.-F., Hu, J. and Li, Z.-L. (2021) The Role of Alveolar Edema in COVID-19. Cells, 10, Article No. 1897. https://doi.org/10.3390/cells10081897
[16]
Wehrwein, E.A., Basu, R., Basu, A., Curry, T.B., Rizza, R.A. and Joyner, M.J. (2010) Hyperoxia Blunts Counterregulation during Hypoglycaemia in Humans: Possible Role for the Carotid Bodies? The Journal of Physiology, 588, 4593-4601. https://doi.org/10.1113/jphysiol.2010.197491
[17]
Bickler, P.E., Feiner, J.R., Lipnick, M.S. and McKleroy, W. (2021) “Silent” Presentation of Hypoxemia and Cardiorespiratory Compensation in COVID-19. Anesthesiology, 134, 262-269. https://doi.org/10.1097/ALN.0000000000003578
[18]
Tobin, M.J., Laghi, F. and Jubran, A. (2020) Why COVID-19 Silent Hypoxemia Is Baffling to Physicians. American Journal of Respiratory and Critical Care Medicine, 202, 356-360. https://doi.org/10.1164/rccm.202006-2157CP
[19]
Savulescu, J., Vergano, M., Craxì, L. and Wilkinson, D. (2020) An Ethical Algorithm for Rationing Life-Sustaining Treatment during the COVID-19 Pandemic. British Journal of Anaesthesia, 125, 253-258. https://doi.org/10.1016/j.bja.2020.05.028
[20]
Harbut, P., Prisk, G.K., Lindwall, R., Hamzei, S., Palmgren, J., Farrow, C.E., Hedenstierna, G., Amis, T.C., Malhotra, A., Wagner, P.D. and Kairaitis, K. (2023) Intrapulmonary Shunt and Alveolar Dead Space in a Cohort of Patients with Acute COVID-19 Pneumonitis and Early Recovery. European Respiratory Journal, 61, Article ID: 2201117. https://doi.org/10.1183/13993003.01117-2022
[21]
Böning, D., Kuebler, W.M. and Bloch, W. (2021) The Oxygen Dissociation Curve of Blood in COVID-19. American Journal of Physiology-Lung Cellular and Molecular Physiology, 321, L349-L357. https://doi.org/10.1152/ajplung.00079.2021
[22]
Liu, W. and Li, H. (2022) COVID-19: Attacks the 1-Beta Chain of Hemoglobin to Disrupt Respiratory Function and Escape Immunity. https://doi.org/10.26434/chemrxiv-2021-dtpv3-v11
[23]
Mason, R.J. (2020) Pathogenesis of COVID-19 from a Cell Biology Perspective. European Respiratory Journal, 55, Article ID: 2000607. https://doi.org/10.1183/13993003.00607-2020
[24]
Sedaghat, A.R., Gengler, I. and Speth, M.M. (2020) Olfactory Dysfunction: A Highly Prevalent Symptom of COVID-19 with Public Health Significance. Otolaryngology-Head and Neck Surgery, 163, 12-15. https://doi.org/10.1177/0194599820926464
[25]
Lam, S.Y., Fung, M.L. and Leung, P.S. (2004) Regulation of the Angiotensin-Converting Enzyme Activity by a Time-Course Hypoxia in the Carotid Body. Journal of Applied Physiology (Bethesda, Md.: 1985), 96, 809-813. https://doi.org/10.1152/japplphysiol.00684.2003
[26]
Gengler, I., Wang, J.C., Speth, M.M. and Sedaghat, A.R. (2020) Sinonasal Pathophysiology of SARS-CoV-2 and COVID-19: A Systematic Review of the Current Evidence. Laryngoscope Investigative Otolaryngology, 5, 354-359. https://doi.org/10.1002/lio2.384
[27]
Komorowski, M. and Aberegg, S.K. (2020) Using Applied Lung Physiology to Understand COVID-19 Patterns. British Journal of Anaesthesia, 125, 250-253. https://doi.org/10.1016/j.bja.2020.05.019
[28]
Ruaro, B., Confalonieri, P., Pozzan, R., Tavano, S., Mondini, L., Baratella, E., Pagnin, A., Lerda, S., Geri, P., Biolo, M., Confalonieri, M. and Salton, F. (2022) Severe COVID-19 ARDS Treated by Bronchoalveolar Lavage with Diluted Exogenous Pulmonary Surfactant as Salvage Therapy: In Pursuit of the Holy Grail? Journal of Clinical Medicine, 11, Article No. 3577. https://doi.org/10.3390/jcm11133577
[29]
West, J.B. (2011) Causes of and Compensations for Hypoxemia and Hypercapnia. Comprehensive Physiology, 1, 1541-1553. https://doi.org/10.1002/cphy.c091007
[30]
Lang, M., Som, A., Carey, D., Reid, N., Mendoza, D.P., Flores, E.J., Li, M.D., Shepard, J.-A.O. and Little, B.P. (2020) Pulmonary Vascular Manifestations of COVID-19 Pneumonia. Radiology: Cardiothoracic Imaging, 2, e200277. https://doi.org/10.1148/ryct.2020200277
[31]
Gattinoni, L., Chiumello, D., Caironi, P., Busana, M., Romitti, F., Brazzi, L. and Camporota, L. (2020) COVID-19 Pneumonia: Different Respiratory Treatments for Different Phenotypes? Intensive Care Medicine, 46, 1099-1102. https://doi.org/10.1007/s00134-020-06033-2
[32]
Gattinoni, L., Coppola, S., Cressoni, M., Busana, M., Rossi, S. and Chiumello, D. (2020) COVID-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine, 201, 1299-1300. https://doi.org/10.1164/rccm.202003-0817LE
[33]
Baertsch, N.A., Severs, L.J., Anderson, T.M. and Ramirez, J.-M. (2019) A Spatially Dynamic Network Underlies the Generation of Inspiratory Behaviors. Proceedings of the National Academy of Sciences, 116, 7493-7502. https://doi.org/10.1073/pnas.1900523116
[34]
Costa, R., Navalesi, P., Cammarota, G., Longhini, F., Spinazzola, G., Cipriani, F., Ferrone, G., Festa, O., Antonelli, M. and Conti, G. (2017) Remifentanil Effects on Respiratory Drive and Timing during Pressure Support Ventilation and Neurally Adjusted Ventilatory Assist. Respiratory Physiology & Neurobiology, 244, 10-16. https://doi.org/10.1016/j.resp.2017.06.007
[35]
Lumb, A.B. and Thomas, C.R. (2020) Nunn’s Applied Respiratory Physiology eBook: Nunn’s Applied Respiratory Physiology eBook. Elsevier Health Sciences, Amsterdam.
[36]
Bisgard, G.E. (2000) Carotid Body Mechanisms in Acclimatization to Hypoxia. Respiration Physiology, 121, 237-246. https://doi.org/10.1016/s0034-5687(00)00131-6
[37]
Forster, H.V. and Smith, C.A. (2010) Contributions of Central and Peripheral Chemoreceptors to the Ventilatory Response to CO2/H+. Journal of Applied Physiology, 108, 989-994. https://doi.org/10.1152/japplphysiol.01059.2009
[38]
Tan, B.-H., Zhang, Y., Gui, Y., Wu, S. and Li, Y.-C. (2020) The Possible Impairment of Respiratory-Related Neural Loops May Be Associated with the Silent Pneumonia Induced by SARS-CoV-2. Journal of Medical Virology, 92, 2269-2271. https://doi.org/10.1002/jmv.26158
[39]
Kumar, P. and Prabhakar, N.R. (2012) Peripheral Chemoreceptors: Function and Plasticity of the Carotid Body. Comprehensive Physiology, 2, 141-219. https://doi.org/10.1002%2Fcphy.c100069
[40]
Duffin, J. and McAvoy, G.V. (1988) The Peripheral-Chemoreceptor Threshold to Carbon Dioxide in Man. The Journal of Physiology, 406, 15-26. https://doi.org/10.1113/jphysiol.1988.sp017365
[41]
Bruce, E.N. and Cherniack, N.S. (1987) Central Chemoreceptors. Journal of Applied Physiology (Bethesda, Md.: 1985), 62, 389-402. https://doi.org/10.1152/jappl.1987.62.2.389
[42]
Prabhakar, N.R. (2000) Oxygen Sensing by the Carotid Body Chemoreceptors. Journal of Applied Physiology, 88, 2287-2295. https://doi.org/10.1152/jappl.2000.88.6.2287
[43]
Liu, X., Liu, X., Xu, Y., Xu, Z., Huang, Y., Chen, S., Li, S., Liu, D., Lin, Z. and Li, Y. (2020) Ventilatory Ratio in Hypercapnic Mechanically Ventilated Patients with COVID-19-Associated Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine, 201, 1297-1299. https://doi.org/10.1164/rccm.202002-0373LE
[44]
Yoshida, T., Torsani, V., Gomes, S., De Santis, R.R., Beraldo, M.A., Costa, E.L.V., Tucci, M.R., Zin, W.A., Kavanagh, B.P. and Amato, M.B.P. (2013) Spontaneous Effort Causes Occult Pendelluft during Mechanical Ventilation. American Journal of Respiratory and Critical Care Medicine, 188, 1420-1427. https://doi.org/10.1164/rccm.201303-0539OC
[45]
Dutschmann, M. and Dick, T.E. (2012) Pontine Mechanisms of Respiratory Control. Comprehensive Physiology, 2, 2443-2469. https://doi.org/10.1002/cphy.c100015
[46]
Ikeda, K., Kawakami, K., Onimaru, H., Okada, Y., Yokota, S., Koshiya, N., Oku, Y., Iizuka, M. and Koizumi, H. (2017) The Respiratory Control Mechanisms in the Brainstem and Spinal Cord: Integrative Views of the Neuroanatomy and Neurophysiology. The Journal of Physiological Sciences, 67, 45-62. https://doi.org/10.1007/s12576-016-0475-y
[47]
Jensen, V.N., Alilain, W.J. and Crone, S.A. (2020) Role of Propriospinal Neurons in Control of Respiratory Muscles and Recovery of Breathing Following Injury. Frontiers in Systems Neuroscience, 13, Article No. 84. https://www.frontiersin.org/articles/10.3389/fnsys.2019.00084
[48]
Brandenburg, J.E., Fogarty, M.J. and Sieck, G.C. (2020) Why Individuals with Cerebral Palsy Are at Higher Risk for Respiratory Complications from COVID-19. Journal of Pediatric Rehabilitation Medicine, 13, 317-327. https://doi.org/10.3233/PRM-200746
[49]
Chang, R.B., Strochlic, D.E., Williams, E.K., Umans, B.D. and Liberles, S.D. (2015) Vagal Sensory Neuron Subtypes That Differentially Control Breathing. Cell, 161, 622-633. https://doi.org/10.1016/j.cell.2015.03.022
[50]
Neumann, B., Schulte-Mattler, W., Brix, S., Pöschl, P., Jilg, W., Bogdahn, U., Steinbrecher, A. and Kleiter, I. (2016) Autonomic and Peripheral Nervous System Function in Acute Tick-Borne Encephalitis. Brain and Behavior, 6, e00485. https://doi.org/10.1002/brb3.485
[51]
Giannitsi, S., Tsinivizov, P., Poulimenos, L.E., Kallistratos, M.S., Varvarousis, D., Manolis, A.J., Tsamakis, K., Rizos, E., Spandidos, D.A., Tsiptsios, D. and Triantafyllis, A.S. (2020) [Case Report] Stress Induced (Takotsubo) Cardiomyopathy Triggered by the COVID19 Pandemic. Experimental and Therapeutic Medicine, 20, 2812-2814. https://doi.org/10.3892/etm.2020.8968
[52]
Huang, Y., Tan, C., Wu, J., Chen, M., Wang, Z., Luo, L., Zhou, X., Liu, X., Huang, X., Yuan, S., Chen, C., Gao, F., Huang, J., Shan, H. and Liu, J. (2020) Impact of Coronavirus Disease 2019 on Pulmonary Function in Early Convalescence Phase. Respiratory Research, 21, Article No. 163. https://doi.org/10.1186/s12931-020-01429-6
[53]
Del Rio, R., Marcus, N.J. and Inestrosa, N.C. (2020) Potential Role of Autonomic Dysfunction in Covid-19 Morbidity and Mortality. Frontiers in Physiology, 11, Article ID: 561749. https://www.frontiersin.org/articles/10.3389/fphys.2020.561749
[54]
De Ferrari, G.M., Stolen, C., Tuinenburg, A.E., Wright, D.J., Brugada, J., Butter, C., Klein, H., Neuzil, P., Botman, C., Castel, M.A., D’Onofrio, A., de Borst, G.J., Solomon, S., Stein, K.M., Schubert, B., Stalsberg, K., Wold, N., Ruble, S. and Zannad, F. (2017) Long-Term Vagal Stimulation for Heart Failure: Eighteen Month Results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) Trial. International Journal of Cardiology, 244, 229-234. https://doi.org/10.1016/j.ijcard.2017.06.036
[55]
Li, X. and Ma, X. (2020) Acute Respiratory Failure in COVID-19: Is It “Typical” ARDS? Critical Care, 24, Article No. 198. https://doi.org/10.1186/s13054-020-02911-9
[56]
Sanches Santos Rizzo Zuttion, M., Moore, S.K.L., Chen, P., Beppu, A.K. and Hook, J.L. (2022) New Insights into the Alveolar Epithelium as a Driver of Acute Respiratory Distress Syndrome. Biomolecules, 12, Article No. 1273. https://doi.org/10.3390/biom12091273
[57]
Hsieh, Y.-H., Litvin, D.G., Zaylor, A.R., Nethery, D.E., Dick, T.E. and Jacono, F.J. (2020) Brainstem Inflammation Modulates the Ventilatory Pattern and Its Variability after Acute Lung Injury in Rodents. The Journal of Physiology, 598, 2791-2811. https://doi.org/10.1113/JP279177
[58]
Grieb, P., Swiatkiewicz, M., Prus, K. and Rejdak, K. (2021) Hypoxia May Be a Determinative Factor in COVID-19 Progression. Current Research in Pharmacology and Drug Discovery, 2, Article ID: 100030. https://doi.org/10.1016/j.crphar.2021.100030
[59]
Brouqui, P., Amrane, S., Million, M., Cortaredona, S., Parola, P., Lagier, J.-C. and Raoult, D. (2021) Asymptomatic Hypoxia in COVID-19 Is Associated with Poor Outcome. International Journal of Infectious Diseases, 102, 233-238. https://doi.org/10.1016/j.ijid.2020.10.067
[60]
Galwankar, S.C., Paladino, L., Gaieski, D.F., Nanayakkara, K., Di Somma, S., Grover, J. and Stawicki, S.P. (2020) Management Algorithm for Subclinical Hypoxemia in Coronavirus Disease-2019 Patients: Intercepting the “Silent Killer”. Journal of Emergencies, Trauma, and Shock, 13, 110-113. https://doi.org/10.4103/JETS.JETS_72_20
[61]
Azar, W.S., Njeim, R., Fares, A.H., Azar, N.S., Azar, S.T., El Sayed, M. and Eid, A.A. (2020) COVID-19 and Diabetes Mellitus: How One Pandemic Worsens the Other. Reviews in Endocrine and Metabolic Disorders, 21, 451-463. https://doi.org/10.1007/s11154-020-09573-6
[62]
Mao, L., Jin, H., Wang, M., Hu, Y., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y. and Wang, D. (2020) Neurologic Manifestations of Hospitalized Patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurology, 77, 683-690. https://pubmed.ncbi.nlm.nih.gov/32275288
[63]
Simonson, T.S., Baker, T.L., Banzett, R.B., Bishop, T., Dempsey, J.A., Feldman, J.L., Guyenet, P.G., Hodson, E.J., Mitchell, G.S., Moya, E.A., Nokes, B.T., Orr, J.E., Owens, R.L., Poulin, M., Rawling, J.M., Schmickl, C.N., Watters, J.J., Younes, M. and Malhotra, A. (2021) Silent Hypoxaemia in COVID-19 Patients. The Journal of Physiology, 599, 1057-1065. https://doi.org/10.1113/JP280769
[64]
Dargent, A., Hombreux, A., Roccia, H., Argaud, L., Cour, M. and Guérin, C. (2022) Feasibility of Non-Invasive Respiratory Drive and Breathing Pattern Evaluation Using CPAP in COVID-19 Patients. Journal of Critical Care, 69, Article ID: 154020. https://doi.org/10.1016/j.jcrc.2022.154020
[65]
Frizzelli, A., Di Spigno, F., Moderato, L., Halasz, G., Aiello, M., Tzani, P., Manari, G., Calzetta, L., Pisi, R., Pelà, G., Piepoli, M. and Chetta, A. (2022) An Impairment in Resting and Exertional Breathing Pattern May Occur in Long-COVID Patients with Normal Spirometry and Unexplained Dyspnoea. Journal of Clinical Medicine, 11, Article No. 7388. https://doi.org/10.3390/jcm11247388
[66]
Shi, H., Han, X., Jiang, N., Cao, Y., Alwalid, O., Gu, J., Fan, Y. and Zheng, C. (2020) Radiological Findings from 81 Patients with COVID-19 Pneumonia in Wuhan, China: A Descriptive Study. The Lancet Infectious Diseases, 20, 425-434. https://doi.org/10.1016/S1473-3099(20)30086-4
[67]
Onders, R.P., Katirji, B., Schilz, R., Nemunaitis, G., Elmo, M. and Ignagni, A. (2007) Continuous Ambulatory Diaphragm EMG Measurements: Assessing Respiratory Control and Function Utilizing the Diaphragm Pacing Stimulation (DPS) System. Chest, 132, 649C. https://doi.org/10.1378/chest.132.4_MeetingAbstracts.649c
[68]
Jolley, C.J., Luo, Y.-M., Steier, J., Reilly, C., Seymour, J., Lunt, A., Ward, K., Rafferty, G.F., Polkey, M.I. and Moxham, J. (2009) Neural Respiratory Drive in Healthy Subjects and in COPD. European Respiratory Journal, 33, 289-297. https://doi.org/10.1183/09031936.00093408
[69]
Spiesshoefer, J., Friedrich, J., Regmi, B., Geppert, J., Jörn, B., Kersten, A., Giannoni, A., Boentert, M., Marx, G., Marx, N., Daher, A. and Dreher, M. (2022) Diaphragm Dysfunction as a Potential Determinant of Dyspnea on Exertion in Patients 1 Year after COVID-19-Related ARDS. Respiratory Research, 23, Article No. 187. https://doi.org/10.1186/s12931-022-02100-y
[70]
Laviolette, L. and Laveneziana, P. (2014) Dyspnoea: A Multidimensional and Multidisciplinary Approach. European Respiratory Journal, 43, 1750-1762. https://doi.org/10.1183/09031936.00092613
[71]
Mitchell, G.S. and Johnson, S.M. (2003) Invited Review: Neuroplasticity in Respiratory Motor Control. Journal of Applied Physiology, 94, 358-374. https://doi.org/10.1152/japplphysiol.00523.2002
[72]
Hopkinson, N.S., Sharshar, T., Dayer, M.J., Lofaso, F., Moxham, J. and Polkey, M.I. (2012) The Effect of Acute Non-Invasive Ventilation on Corticospinal Pathways to the Respiratory Muscles in Chronic Obstructive Pulmonary Disease. Respiratory Physiology & Neurobiology, 183, 41-47. https://doi.org/10.1016/j.resp.2012.05.018
[73]
Faisal, A., Alghamdi, B.J., Ciavaglia, C.E., Elbehairy, A.F., Webb, K.A., Ora, J., Neder, J.A. and O’Donnell, D.E. (2016) Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders. American Journal of Respiratory and Critical Care Medicine, 193, 299-309. https://doi.org/10.1164/rccm.201504-0841OC
[74]
Elbehairy, A.F., Faisal, A., McIsaac, H., Domnik, N.J., Milne, K.M., James, M.D., Neder, J.A. and O’Donnell, D.E. (2021) Mechanisms of Orthopnoea in Patients with Advanced COPD. European Respiratory Journal, 57, Article ID: 2000754. https://doi.org/10.1183/13993003.00754-2020
[75]
Satıcı, C., Aydın, Ş., Tuna, L., Köybaşı, G. and Koşar, F. (2021) Electromyographic and Sonographic Assessment of Diaphragm Dysfunction in Patients Who Recovered from the COVID-19 Pneumonia. Tuberkuloz ve Toraks, 69, 425-428. https://doi.org/10.5578/tt.20219718
[76]
Ora, J., Rogliani, P., Dauri, M. and O’Donnell, D. (2021) Happy Hypoxemia, or Blunted Ventilation? Respiratory Research, 22, Article No. 4. https://doi.org/10.1186/s12931-020-01604-9
[77]
Hudson, A.L. and Laveneziana, P. (2015) Do We “Drive” Dyspnoea? European Respiratory Journal, 45, 301-304. https://doi.org/10.1183/09031936.00223314
[78]
Garg, D., Srivastava, A.K. and Dhamija, R.K. (2020) Beyond Fever, Cough and Dyspnea: The Neurology of COVID-19. JAPI: Journal of the Association of Physicians of India, 68, 62-66.
[79]
McCartney, A., Phillips, D., James, M., Chan, O., Neder, J.A., de-Torres, J.P., Domnik, N.J. and Crinion, S.J. (2022) Ventilatory Neural Drive in Chronically Hypercapnic Patients with COPD: Effects of Sleep and Nocturnal Noninvasive Ventilation. European Respiratory Review, 31, Article ID: 220069. https://doi.org/10.1183/16000617.0069-2022
[80]
Singh, B., Panizza, J.A. and Finucane, K.E. (2005) Diaphragm Electromyogram Root Mean Square Response to Hypercapnia and Its Intersubject and Day-to-Day Variation. Journal of Applied Physiology, 98, 274-281. https://doi.org/10.1152/japplphysiol.01380.2003
[81]
Crooks, C.J., West, J., Morling, J.R., Simmonds, M., Juurlink, I., Briggs, S., Cruickshank, S., Hammond-Pears, S., Shaw, D., Card, T.R., Marshall, C.R. and Fogarty, A.W. (2023) Respiratory Rate Responses to Both Hypercapnia and Acidemia Are Modified by Age in Patients with Acidosis. Respiratory Physiology & Neurobiology, 315, 104098. https://doi.org/10.1016/j.resp.2023.104098
[82]
Oudkerk, M., Büller, H.R., Kuijpers, D., van Es, N., Oudkerk, S.F., McLoud, T., Gommers, D., van Dissel, J., Ten Cate, H. and van Beek, E.J. (2020) Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology, 297, E216-E222. https://doi.org/10.1148/radiol.2020201629
[83]
McGonagle, D., O’Donnell, J.S., Sharif, K., Emery, P. and Bridgewood, C. (2020) Immune Mechanisms of Pulmonary Intravascular Coagulopathy in COVID-19 Pneumonia. The Lancet Rheumatology, 2, e437-e445. https://doi.org/10.1016/S2665-9913(20)30121-1
[84]
Yang, K.L. and Tobin, M.J. (1991) A Prospective Study of Indexes Predicting the Outcome of Trials of Weaning from Mechanical Ventilation. New England Journal of Medicine, 324, 1445-1450. https://doi.org/10.1056/NEJM199105233242101
[85]
Shahbaz, S., Xu, L., Osman, M., Sligl, W., Shields, J., Joyce, M., Tyrrell, D.L., Oyegbami, O. and Elahi, S. (2021) Erythroid Precursors and Progenitors Suppress Adaptive Immunity and Get Invaded by SARS-CoV-2. Stem Cell Reports, 16, 1165-1181. https://doi.org/10.1016/j.stemcr.2021.04.001
[86]
Beyerstedt, S., Casaro, E.B. and Rangel, é.B. (2021) COVID-19: Angiotensin-Converting Enzyme 2 (ACE2) Expression and Tissue Susceptibility to SARS-CoV-2 Infection. European Journal of Clinical Microbiology & Infectious Diseases, 40, 905-919. https://doi.org/10.1007/s10096-020-04138-6
[87]
Nair, C.V., Sathyapalan, D.T., Moni, M., Suresh, A. and Roshni, P.R. (2021) Happy Hypoxemia: A Perplexing Clinical Entity in Coronavirus Disease 2019. Journal of Applied Pharmaceutical Science, 12, 65-69.
