Inhalation of Heliox as a Potential Treatment for the Acute Respiratory Distress Syndrome (ARDS) caused by Covid-19

Introduction

In December 2019, a group of pneumonia cases were reported in Wuhan, Hubei Province, China. Subsequently, COVID-19 was soon confirmed to be cause for SARS-CoV-2, which has caused a global pandemic. As of December 29, 2020, a total of 81,218,535 patients with COVID-19 and 1,774, 350 deaths have been confirmed worldwide. SARS-CoV-2 infects the lungs by using angiotensin-converting enzyme 2 in type 2 alveolar epithelial cells as a gate. The inflammatory storm after SARS- CoV-2 infection can cause lung cell loss, pulmonary edema, and formation of hyaluronic acid, induces acute respiratory distress syndrome (ARDS), which leads to death. Autopsy report also show that the pathological features in both lungs indicate find- ings similar to that of ARDS or SARS, and Middle East respi- ratory syndrome (MERS) [1,2]. ARDS is the most serious com- plication, accounting for 20.1% of COVID-19, with a mortality rate of 41.1% [3]. Mechanical ventilation is necessary for treat- ing ARDS. Heliox is a helium–oxygen mixture gas. Helium has special physical properties. Heliox by mechanical ventilation can reduce the work of breathing, improve compliance, promote removal of carbon dioxide and improve oxygenation. There- fore, heliox could become a lung-protective ventilation strate- gy. Another potential benefit of heliox is its anti-inflammatory effect. This effect not only effectively reduces the inflammatory response to lung damage, but also inhibits overflow of inflam- matory cytokines or chemokines, and reduces the occurrence of a systemic cytokine storm. Heliox also protects nerves and the heart during ischemia-reperfusion. Therefore, heliox is likely to have a therapeutic potential for ARDS caused by COVID-19.

Properties and Safety of Helium

Helium is a colorless, odorless, and non-toxic inert monatomic gas, which does not react with other gases in the body and has no pharmacological activity. Helium is also the lightest noble gas and has the lowest melting and boiling points of all elements. Helium has a lower density (0.179 g/m) compared with oxygen (1.43 g/m) and nitrogen (1.25 g/m), and its absolute viscosity is 201.8 MP (oxygen: 211.4 MP; general air: 188.5 MP). Under the same conditions, helium flows 2.68 times faster than air. Be- cause the size of the airflow depends on the density and viscosity of each component of the mixture, the physical properties of he- lium reduce respiratory resistance and increase airflow through the lungs [4]. Heliox (Helium-oxygen mixture) has a viscosity similar to, but a density nearly six times lowers than atmospheric air. Because of these unique properties, heliox has a potential ap- plication in respiratory medicine. Heliox gas mixtures are known to be nontoxic, non-carcinogenic, and have no lasting effects on any human organs. Due to its lower density, inhalation of he- liox results in significantly lower turbulence, particularly in the more distal portions of the lung. This effect translates to a greater proportion of laminar flow and lower overall airway resistance. The decreased turbulence effect results in increased flow rates by up to 50% during heliox inhalation [5]. This decreased turbu- lence remained evident even when airflow was restricted, as in the case of obstructive lung disease. Heliox has been applied to various respiratory diseases in adults for more than 70 years with no adverse effects with no serious complications reported [6]. A case report showed that the combination of helium and oxygen is safe during pregnancy [7]. A lower density of helium causes inaccurately high readings from flow meters that are calibrated for air and/or oxygen [8,9]. Therefore, the flow transducer with- in the ventilator needs adjustment to correctly measure flow to prevent discrepancy in exhaled tidal volumes and misinterpreted improvement in carbon dioxide (CO2) clearance.

Principle of Treatment of ARDS

Since the outbreak of SARS-CoV in 2002 and MERS-CoV in 2012, the emergence of SARS-CoV-2 marks the third introduc- tion of a highly pathogenic and pandemic coronavirus into hu- mans in the 21st century. SARS-CoV-2 is a beta coronavirus, and two other known beta CoVs are SARS and MERS. All these coronaviruses can lead to severe and potentially fatal respiratory infections, mainly caused by lung cell loss, pulmonary edema, and formation of hyaluronic acid. This then leads to ARDS caus- ing death. Autopsy report show confirm the lesions in both lungs as seen in ARDS [1,2]. Therefore, development of more effec- tive mechanical strategies to reduce the mortality of ARDS is not only an urgent need in the current outbreak of novel coronavirus, but also a long-term need to reduce the mortality of viral pneu- monia worldwide [3]. Heliox due to its unique properties may be an ideal gas in ARDS caused by SARS-COVID-2 in reducing the work of breathing, improving compliance and inflammation and reducing morbidity and mortality [8]. During ventilation with heliox, lower driving pressures are necessary to distribute oxygen to the distal alveoli to improve oxygenation and CO2 diffusion. This will result in better gas exchange in ARDS [10]. Therefore, Heliox is a better lung-protective ventilation strategy for ARDS.

Animal Models

In a study of neonatal piglets where ARDS was induced by sa- line lavage, three types of aeration therapy were evaluated, in- cluding oxygen-enriched air and heliox (60% oxygen/40% heli- um and 40% oxygen/60% helium) [11]. The results showed that the partial pressure of carbon dioxide (PaCO2), in the two he- liox groups decreased on an average of 10.5 and 20.3 mm Hg. A modest improvement in oxygenation was observed with the 40% helium mixture. These results indicated that heliox improved oxygenation and elimination of carbon dioxide. Similar results were found in other animal models of ventilation in ARDS. Heliox significantly improved gas exchange, reduced the need for oxygen, and decreased PaCO2 compared with the pediatric swine ventilated with nitrogen [12,13].

Clinical Study

Heliox has been clinically studied for more than 70 years to reduce airway resistance and improve ventilation. Two adult studies reported results in patients who were diagnosed to have bronchiolitis obliterans syndrome and acute respiratory failure following lung transplantation and were treated with 60% heliox administered either via bi-level positive airway pressure (BiPAP) or high-frequency oscillatory ventilation (HFOV) [14]. This re- port showed that heliox ventilation increased pH and decreased PaCO2. In a randomized, controlled study of newborn respirato- ry distress syndrome, 51 newborns were randomly divided into two groups [15]. Both groups received nasal continuous posi- tive airway pressure (NCPAP). The first group received NCPAP plus Heliox 21 while control group received NCPAP with stan- dard medical air. The intervention group (n=27) received 80% heliox and the control group (n=24) received nasal continuous positive airway pressure with medical air. This study showed that NCPAP with heliox treatment significantly decreased the risk of intubation for mechanical ventilation (14.8% vs 45.8%; P=0.029, relative risk 0.32, 95% confidence interval 0.12–0.88) and decreased the requirement for surfactant (11.1% vs 43.5%; P=0.021, relative risk 0.26, 95% confidence interval 0.08-0.82). In clinical studies on the treatment of ARDS in adults and chil- dren it has been shown that a helium–oxygen mixture improves gas exchange, promotes elimination of CO2, and reduces the rate intubation r. Therefore, using a helium–oxygen mixture is a rea- sonable intervention for treating ARDS caused by COVID-19.

Potential Anti-Inflammatory Factors

Although the exact pathophysiological mechanism of progres- sion of SARS-CoV-2 infection to ARDS is not fully understood, inflammatory storms are an important cause of ARDS. SARS- CoV-2 infects other cells in the body, especially alveolar mac- rophages. Inflammatory responses are triggered when infected cells die by apoptosis or necrosis [16]. The initial response of an organism to harmful stimuli is acute inflammation and this is characterized by increasing blood flow. This enables plasma and leukocytes to reach extra-vascular sites of injury, elevating local temperature and causing pain. An acute inflammatory response is also marked by activation of pro-inflammatory cytokines or chemokines. These pro-inflammatory cytokines or chemokines can lead to recruitment of inflammatory cells [17,18]. For severe inflammation associated with a cytokine storm, more serious pathological changes are observed, such as diffuse alveolar dam- age, hyaline membrane formation, fibrin exudates, and fibrotic healing. Therefore, ARDS develops and the patient eventually succumb to the infection. These observations are confirmed in autopsy reports where both lungs were affected consistent with the presence of ARDS caused by COVID-19, similar to SARS- CoV and MERS-CoV [19]. Management of ARDS was inves tigated with the use of heliox in an experimental models. The lungs of two groups of rats were dissected after inhalation. This study histopathological showed the effectiveness of heliox in decreasing infiltration of neutrophils, interstitial/intra-alveo- lar edema, perivascular and/or intra-alveolar hemorrhage, and HM formation in ARDS [13]. Similar results were found during continuous positive airway pressure ventilation using a neonatal pig model in which ARDS was induced by oleic acid [13]. In the lung tissue of pigs that were ventilated for 4 h, interleukin-8 and myeloperoxidase levels, which are indicators of neutrophil activation, were lower in pigs that were ventilated with heliox compared with those ventilated with nitrogen.

Protection of Nerves and the Heart

Recent studies of cells, isolated tissues, animals, and humans have shown that helium has profound biological effects as fol- lows. When helium is applied before, during, or after an isch- emic event, it reduces cellular damage, known as “organ condi- tioning”. Helium also exerts cellular effects in vitro and in vivo. Helium reduces ischemia-reperfusion damage in cardiac and neuronal tissue [20-24].

Helium induced changes in circulating caveolin in mice suggest a novel mechanism of cardiac protection [25]. In a rat model of resuscitation, one study examined the effects of helium pre- and post-conditioning on the brain and heart [22]. This study showed that helium treatment resulted in significantly less apop- tosis. Therefore, according to the above-mentioned animal ex- periments, heliox has a protective effect on important organs of nerves and the heart. After SARS-CoV-2 infection, the body shows an inflammatory storm, resulting in formation of ARDS, often with multiple organ damage, such as the heart and nervous system. The use of heliox inhalation therapy without mechanical ventilation especially in early cases of COVID 19 chest infec- tion as a protective mechanism to avoid the needs for invasive ventilation is a novel concept and requires further investigation. Use of heliox not only protects the lungs, but also has an import- ant biological role in protecting the heart and nerves as shown in animal experiments.

Discussion and Prospects

There are still some questions to be considered in determining the use of a helium–oxygen mixture in treating patients with COVID-19 with ARDS. For ventilation of severely anoxic pa- tients with ARDS, the percentage of oxygen in the helium–ox- ygen mixture needs to be determined. The time to use the heli- um–oxygen mixture also needs to be determined. Furthermore, there is the issue of whether clinical outcomes are consistent with animal models. Additionally, possible long-term complica- tions associated with the use of helium–oxygen mixtures need to be addressed. More large-scale, randomized, well-designed, pro- spective studies are required to address these issues. The global COVID-19 pandemic is accelerating. In the absence of specific treatment, inhaling helium–oxygen mixtures on mechanical ven- tilation has great potential, although its efficacy is controversial. Generally, pre-clinical and clinical studies on treatment of ARDS with a helium–oxygen mixture have shown encouraging positive effects, including improved ventilation, improved lung compliance, reduced inflammation, and protection of vital or gans. However, data on clinical outcomes are limited, and we expect more well-designed prospective studies in the future.

Author Contributions

Ma Juan, the first author, wrote the paper. Liu Hui-min, the cor- responding author, designed and modified the Manuscript. Yuan Shi drafted the work. Qing Mao approved the version to be pub- lished.

Funding

This work was sponsored by Mission Statement-A Construction Plan of Military Bio-Safety: Study on the integration of early warning, intervention and treatment of severe viral infectious diseases(17SAZ09).

Ethical Approval

The study protocol was approved by the Ethics Committee of Southwest Hospital (document No.KY201989) and was carried out in accordance with the principles of the Declaration of Hel- sinki, 1964.

Informed Consent

Informed consent was obtained from all individual participants included in the study. All authors declare that the submitted work has not been published before (neither in English nor in any other language) and that the work is not under consideration for publication elsewhere.

References

1. Lai, C. C., Shih, T. P., Ko, W. C., Tang, H. J., & Hsueh, P.R. (2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. International journal of antimicrobial agents, 55(3), 105924.
2. Ramanathan, K., Antognini, D., Combes, A., Paden, M., Zakhary, B., & et al. (2020). Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious dis- eases. The Lancet Respiratory Medicine, 8(5), 518-526.
3. Matthay, M. A., Aldrich, J. M., & Gotts, J. E. (2020). Treat- ment for severe acute respiratory distress syndrome from COVID-19. The Lancet Respiratory Medicine, 8(5), 433- 434.
4. Berganza, C. J., & Zhang, J. H. (2013). The role of heliumgas in medicine. Medical gas research, 3(1), 1-7.
5. Hashemian, S. M., & Fallahian, F. (2014). The use of heliox in critical care. International journal of critical illness and injury science, 4(2), 138-142.
6. Beurskens, C. J., Wösten-van Asperen, R. M., Preckel, B., & Juffermans, N. P. (2015). The potential of heliox as a ther- apy for acute respiratory distress syndrome in adults and children: a descriptive review. Respiration, 89(2), 166-174.
7. George, R., Berkenbosch, J. W., Fraser, R. F., & Tobias, J.D. (2001). Mechanical ventilation during pregnancy using a helium–oxygen mixture in a patient with respiratory failure due to status asthmaticus. Journal of Perinatology, 21(6), 395-398.
8. Hess, D. R., Fink, J. B., Venkataraman, S. T., Kim, I. K., Myers, T. R., & et al. (2006). The history and physics of heliox. Respiratory care, 51(6), 608-612.
9. Villar, J., Blanco, J., Añón, J. M., Santos-Bouza, A., Blanch, L., & et al. (2011). The ALIEN study: incidence and out- come of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive care medicine, 37(12), 1932-1941.
10. Gentile, M. A. (2011). Inhaled medical gases: more tobreathe than oxygen. Respiratory care, 56(9), 1341-1359.
11. Katz, A., Gentile, M. A., Craig, D. M., Quick, G., Meliones,J. N., & et al. (2001). Heliox improves gas exchange during high-frequency ventilation in a pediatric model of acute lung injury. American journal of respiratory and critical care medicine, 164(2), 260-264.
12. Katz, A. L., Gentile, M. A., Craig, D. M., Quick, G., & Cheifetz, I. M. (2003). Heliox does not affect gas exchange during high-frequency oscillatory ventilation if tidal volume is held constant. Critical care medicine, 31(7), 2006-2009.
13. Nawab, U. S., Touch, S. M., Irwin-Sherman, T., Blackson,T. J., Greenspan, J. S., & et al. (2005). Heliox attenuates lung inflammation and structural alterations in acute lung injury. Pediatric pulmonology, 40(6), 524-532.
14. Kirkby, S., Robertson, M., Evans, L., Preston, T. J., Tobias,J. D., & et al. (2013). Helium-oxygen mixture to facilitate ventilation in patients with bronchiolitis obliterans syn- drome after lung transplantation. Respiratory care, 58(4), e42-e46.
15. Colnaghi, M., Pierro, M., Migliori, C., Ciralli, F., Matassa,P. G., & et al. (2012). Nasal continuous positive airway pressure with heliox in preterm infants with respiratory dis- tress syndrome. Pediatrics, 129(2), e333-e338.
16. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., & et al. (2020). Clinical features of patients infected with 2019 nov- el coronavirus in Wuhan, China. The lancet, 395(10223), 497-506.
17. World Health Organization. (2020). Infection prevention and control during health care when novel coronavirus (nCoV) infection is suspected: interim guidance, 25 January2020 (No. WHO/2019-nCoV/IPC/2020.2). World Health Organization.
18. Liu, Q., Zhou, Y. H., & Yang, Z. Q. (2016). The cytokine storm of severe influenza and development of immunomod- ulatory therapy. Cellular & molecular immunology, 13(1), 3-10.
19. Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., & et al. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet respiratory medicine, 8(4), 420-422.
20. Oei, G. T., Weber, N. C., Hollmann, M. W., & Preckel, B. (2010). Cellular effects of helium in different organs. The Journal of the American Society of Anesthesiologists, 112(6), 1503-1510.
21. C Weber, N., F Smit, K., W Hollmann, M., & Preckel, B. (2015). Targets involved in cardioprotection by the non-an- esthetic noble gas helium. Current Drug Targets, 16(8), 786- 792.
22. Aehling, C., Weber, N. C., Zuurbier, C. J., Preckel, B., Galmbacher, R., & et al. (2018). Effects of combined he- lium pre/post conditioning on the brain and heart in a rat resuscitation model. Acta Anaesthesiologica Scandinavica, 62(1), 63-74.
23. Liu, Y., Xue, F., Liu, G., Shi, X., Liu, Y., & et al. (2011).Helium preconditioning attenuates hypoxia/ischemia-in- duced injury in the developing brain. Brain research, 1376, 122-129.
24. Li, Y., Zhang, P., Liu, Y., Liu, W., & Yin, N. (2016). Helium preconditioning protects the brain against hypoxia/ischemia injury via improving the neurovascular niche in a neonatal rat model. Behavioural Brain Research, 314, 165-172.
25. Weber, N. C., Schilling, J. M., Warmbrunn, M. V., Dhanani, M., Kerindongo, R., & et al. (2019). Helium-induced changes in circulating caveolin in mice suggest a novel mechanism of cardiac protection. International journal of molecular sciences, 20(11), 2640.