Application of nitric oxide in corona virus disease 2019

doi:10.16138/j.1673-6087.2024.01.15

Abstract

Abstract:

The outbreak of coronavirus disease 2019 (COVID-19) has caused a worldwide medical crisis and strained health resources. Nitric oxide (NO) is shown to improve oxygenation, reduce pulmonary artery pressure, and reduce the need for noninvasive ventilation during severe acute respiratory syndrome (SARS) in 2003. SARS coronavirus (SARS-CoV) and SARS-CoV-2 have overlapping genetic structure and pathological characteristics, and NO has antiviral, vasodilator, anticoagulant and anti-inflammatory effects. This article reviewed the application of NO in COVID-19 patients, to provide the treatment strategy for new COVID-19 patients.

Key words: Nitric oxide, Coronavirus disease 2019, Severe acute respiratory syndrome coronavirus 2, Vasodilation, Antivirus

CLC Number:

R511

WANG Yating, HE Chunwei, FU Ziyu, WANG Hui, MA Dedong. Application of nitric oxide in corona virus disease 2019[J]. Journal of Internal Medicine Concepts & Practice, 2024, 19(01): 82-87.

Figures/Tables 1

Table 1

Application of NO in COVID-19 patients

患者	iNO剂量	治疗时间	研究结果	参考文献
自主呼吸轻中型COVID-19 （n=39）	30 ppm	2.1 d	53.9%患者不再需要有创机械通气， SpO₂/ FiO₂较基线提高54.9%；46.1%患者需要机械通气，SpO₂/ FiO₂较基线降低8.6%	[42]
自主呼吸轻中型COVID-19 （n=29）	160 ppm	30 min/次，2次/d，14 d或直到出院或 SARS-CoV-2核酸阴性或连续3 d没有呼吸道症状	呼吸频率降低2次/min，SpO₂/ FiO₂提高49%。治疗期间NO₂最高浓度为1.47 ppm；MetHb最高为4.7%，停用NO 5 min后 MetHb 下降；未发生不良事件和死亡。出院患者在随访28 d内均未出现需要再次住院或COVID-19相关长期后遗症	[43]
轻型COVID-19 （n=80）	2喷/鼻孔，120~140 μL/喷	5~6次/d,9 d	与安慰剂组相比，NO鼻喷雾剂组患者SARS-CoV-2载量24 h内降低95%， 72 h 内降低99%以上	[44]
危重型COVID-19 （n=10）	20 ppm	30 min	PaO₂从（62 ± 9） mmHg升至（64 ± 14） mmHg；PaO₂/FiO₂从（81 ± 19）mmHg升至（84 ± 22 ）mmHg	[47]
危重型COVID-19 （n=34）	10 ppm	30 min	65%患者为应答者	[48]
COVID-19合并ARDS （n=7）	20 ppm	15-30 min	PaO₂从78.2 mmHg升至105 mmHg。肺血管阻力降低9.9%，肺分流未观察到明显变化（39.0% 到40.0%）	[49]
危重型COVID-19合并ARDS （n=9）	20 ppm	1 h	PaO₂/FiO₂从65 mmHg增加到72 mmHg和 SpO₂从53%增加到57%	[50]
COVID-19合并ARDS （n=33）	10~20 ppm	24 h	COVID-19合并ARDS组PaO₂/FiO₂增加3%，其中40%患者 PaO₂/FiO₂增加>10%；非COVID-19的ARDS组PaO₂/FiO₂增加47%，其中 77%患者 PaO₂/FiO₂增加>10%	[51]
危重型COVID-19 （n=193）	80 ppm	前48 h为80 ppm，随后减少至40 ppm，维持在该浓度直至严重低氧血症消退（PaO₂/FiO₂>300 mmHg）	与常规护理组相比，NO组48 hPaO₂/FiO₂改善（分别为-1.4 mmHg和 28.3 mmHg），低氧血症消退时间延长（8.4 d和8.7 d），28 d内低氧血症消退的患者比例增加（17.2%和27.7%），28 d和90 d死亡率无差异，无严重不良事件发生	[52]
危重型COVID-19 （n=16）	20~30 ppm	15~30 min	PaO₂/FiO₂无改善（91.7到91.5 mmHg）。合并右心室功能障碍组PaO₂/FiO₂增加24.1%，无右心室功能障碍组PaO₂/FiO₂增加3.3%	[54]
COVID-19合并ARDS （n=35）	20 ppm	6.1 d	吸入NO后PaO₂/FiO₂增加（13.6到17.4 kPa）和氧合指数降低(20.6到14.4)和死腔率减少(0.28到0.24)。在停止NO治疗后PaO₂/FiO₂与死腔率没有明显改变。65.7%患者为应答者。应答者脑钠肽和高敏肌钙蛋白高于非应答者	[55]
危重型COVID-19合并肺动脉高压（n=5）	10~20 ppm	5~10 d	iNO的患者PaO₂/FiO₂均升高，心功能保持正常，肺动脉压力降低。未iNO治疗的患者发生右心衰竭，肺动脉压力和 PaO₂/FiO₂突然降低，随后死亡	[56]
COVID-19合并 ARDS和重度肺动脉高压（n=1）	15 ppm	7 d	iNO 24 h后，PaO₂/FiO₂从100 mmHg升高至216 mmHg。吸入7d后，PaO₂/FiO₂比值从100 mmHg持续升高至321 mmHg。停止使用NO后，氧合和血流动力学的改善得以保留，允许呼吸脱机。重复经胸超声心动图示，肺动脉高压、三尖瓣反流、右心室收缩力和扩张程度均改善	[57]
COVID-19合并肺动脉高压（n=1）	20 ppm	12~14 h/d, 11 d	患者症状和6 min步行试验改善，肺血管阻力降低，高铁血红蛋白水平保持在参考范围内	[58]
重型或危重COVID-19孕妇（n=6）	160~200 ppm	30 min/次，2次/d，共 39次	患者心肺功能改善，全身氧合增加，呼吸急促减少，并且在入院后的28 d内，5例鼻咽拭子SARS-CoV-2检测结果为2次阴性，3例患者在住院期间共分娩了4名新生儿，且新生儿状况良好，核酸检测为阴性，所有患者对NO耐受性良好	[61]
重型COVID-19孕妇（n=71）	200 ppm	30 min/次，2次/d，共 144次	与常规护理组相比，NO+常规护理组28 d内的吸氧需求减少，住院时间缩短	[62]

Table 1

References 64

[1]	中华预防医学会新型冠状病毒肺炎防控专家组. 新型冠状病毒肺炎流行病学特征的最新认识[J]. 中华流行病学杂志, 2020, 41(2): 139-144.
[2]	Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019[J]. N Engl J Med, 2020, 382(8):727-733. doi: 10.1056/NEJMoa2001017 URL
[3]	Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults[J]. N Engl J Med, 2005, 353(25):2683-2695. doi: 10.1056/NEJMra051884 URL
[4]	Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine[J]. Nature, 1980, 288(5789):373-376. doi: 10.1038/288373a0
[5]	Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine[J]. Nature, 1988, 333(6174) :664-666. doi: 10.1038/333664a0
[6]	罗金梅, 肖毅. 一氧化氮史话[J]. 中华结核和呼吸杂志, 2011, 34(12): 913.
[7]	Gebistorf F, Karam O, Wetterslev J, et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults[J]. Cochrane Database Syst Rev, 2016, 2016(6):CD002787.
[8]	Yu B, Ichinose F, Bloch DB, et al. Inhaled nitric oxide[J]. Br J Pharmacol, 2019, 176(2):246-255. doi: 10.1111/bph.v176.2 URL
[9]	Chen L, Liu P, Gao H, et al. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome[J]. Clin Infect Dis, 2004, 39(10):1531-1535. doi: 10.1086/425357 URL
[10]	Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus[J]. Lancet, 2020, 395(10224):565-574. doi: 10.1016/S0140-6736(20)30251-8 URL
[11]	Ignarro LJ. Nitric oxide is not just blowing in the wind[J]. Br J Pharmacol, 2019, 176(2): 131-134. doi: 10.1111/bph.v176.2 URL
[12]	Moncada S, Higgs A. The L-arginine-nitric oxide pathway[J]. N Engl J Med, 1993, 329(27):2002-2012. doi: 10.1056/NEJM199312303292706 URL
[13]	Bhatraju P, Crawford J, Hall M, et al. Inhaled nitric oxide: Current clinical concepts[J]. Nitric Oxide, 2015, 50:114-128. doi: S1089-8603(15)30013-6 pmid: 26335378
[14]	Emrani J, Ahmed M, Jeffers-Francis L, et al. SARS-COV-2, infection, transmission, transcription, translation, proteins, and treatment[J]. Int J Biol Macromol, 2021, 193 Pt B:1249-1273.
[15]	Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin[J]. Nature, 2020, 579(7798):270-273. doi: 10.1038/s41586-020-2012-7
[16]	Wang Q, Zhang Y, Wu L, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2[J]. Cell, 2020, 181(4):894-904. doi: S0092-8674(20)30338-X pmid: 32275855
[17]	Keyaerts E, Vijgen L, Chen L, et al. Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound[J]. Int J Infect Dis, 2004, 8(4):223-226. doi: 10.1016/j.ijid.2004.04.012 pmid: 15234326
[18]	Akerström S, Mousavi-Jazi M, Klingström J, et al. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus[J]. J Virol, 2005, 79(3):1966-1969. doi: 10.1128/JVI.79.3.1966-1969.2005 pmid: 15650225
[19]	Akerström S, Gunalan V, Keng CT, et al. Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected[J]. Virology, 2009, 395(1):1-9. doi: 10.1016/j.virol.2009.09.007 pmid: 19800091
[20]	Akaberi D, Krambrich J, Ling J, et al. Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro[J]. Redox Biol, 2020, 37:101734. doi: 10.1016/j.redox.2020.101734 URL
[21]	Michel JB. Nitric oxide (NO) and vasomotor tone[J]. Pathol Biol (Paris), 1998, 46(3): 181-189.
[22]	Gattinoni L, Coppola S, Cressoni M, et al. COVID-19 does not lead to a “typical” acute respiratory distress syndrome[J]. Am J Respir Crit Care Med, 2020, 201(10):1299-1300. doi: 10.1164/rccm.202003-0817LE URL
[23]	Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China[J]. JAMA, 2020, 323(11): 1061-1069. doi: 10.1001/jama.2020.1585 URL
[24]	Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome[J]. Lancet Respir Med, 2020, 8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X pmid: 32085846
[25]	Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes?[J]. Intensive Care Med, 2020, 46(6):1099-1102. doi: 10.1007/s00134-020-06033-2 pmid: 32291463
[26]	Lang M, Som A, Mendoza DP, et al. Hypoxaemia related to COVID-19: vascular and perfusion abnormalities on dual-energy CT[J]. Lancet Infect Dis, 2020, 20(12):1365-1366. doi: 10.1016/S1473-3099(20)30367-4 pmid: 32359410
[27]	Cyr AR, Huckaby LV, Shiva SS, et al. Nitric oxide and endothelial dysfunction[J]. Crit Care Clin, 2020, 36(2):307-321. doi: S0749-0704(19)30104-6 pmid: 32172815
[28]	Green SJ. COVID-19 accelerates endothelial dysfunction and nitric oxide deficiency[J]. Microbes Infect, 2020, 22(4-5):149-150. doi: S1286-4579(20)30084-8 pmid: 32425647
[29]	Nicholls JM, Poon LL, Lee KC, et al. Lung pathology of fatal severe acute respiratory syndrome[J]. Lancet, 2003, 361(9371):1773-1778. doi: 10.1016/s0140-6736(03)13413-7 pmid: 12781536
[30]	Ng KH, Wu AK, Cheng VC, et al. Pulmonary artery thrombosis in a patient with severe acute respiratory syndrome[J]. Postgrad Med J, 2005, 81(956):e3.
[31]	Li K, Wohlford-Lenane C, Perlman S, et al. Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4[J]. J Infect Dis, 2016, 213(5):712-722. doi: 10.1093/infdis/jiv499 pmid: 26486634
[32]	Hottz ED, Azevedo-Quintanilha IG, Palhinha L, et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19[J]. Blood, 2020, 136(11): 1330-1341. doi: 10.1182/blood.2020007252 pmid: 32678428
[33]	Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China[J]. N Engl J Med, 2020, 382(18):1708-1720. doi: 10.1056/NEJMoa2002032 URL
[34]	Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19[J]. N Engl J Med, 2020, 383(2):120-128. doi: 10.1056/NEJMoa2015432 URL
[35]	Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation[J]. Blood, 2020, 135(23): 2033-2040. doi: 10.1182/blood.2020006000 pmid: 32339221
[36]	Kuprash DV, Nedospasov SA. Molecular and cellular mechanisms of inflammation[J]. Biochemistry (Mosc), 2016, 81(11):1237-1239. pmid: 27914449
[37]	Korhonen R, Lahti A, Kankaanranta H, et al. Nitric oxide production and signaling in inflammation[J]. Curr Drug Targets Inflamm Allergy, 2005, 4(4):471-479. doi: 10.2174/1568010054526359 URL
[38]	Cinelli MA, Do HT, Miley GP, et al. Inducible nitric oxide synthase: regulation, structure, and inhibition[J]. Med Res Rev, 2020, 40(1):158-189. doi: 10.1002/med.21599 pmid: 31192483
[39]	Darif D, Hammi I, Kihel A, et al. The pro-inflammatory cytokines in COVID-19 pathogenesis: what goes wrong?[J]. Microb Pathog, 2021, 153:104799. doi: 10.1016/j.micpath.2021.104799 URL
[40]	Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell in-fection and endotheliitis in COVID - 19[J]. Lancet, 2020, 395(10234):1417-1418. doi: 10.1016/S0140-6736(20)30937-5 URL
[41]	Guzik TJ, Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation[J]. J Physiol Pharmacol, 2003, 54(4):469-487. pmid: 14726604
[42]	Parikh R, Wilson C, Weinberg J, et al. Inhaled nitric oxide treatment in spontaneously breathing COVID-19 patients[J]. Ther Adv Respir Dis, 2020, 14:1753466620933510.
[43]	Safaee Fakhr B, Di Fenza R, Gianni S, et al. Inhaled high dose nitric oxide is a safe and effective respiratory treat-ment in spontaneous breathing hospitalized patients with COVID-19 pneumonia[J]. Nitric Oxide, 2021, 116: 7-13. doi: 10.1016/j.niox.2021.08.003 pmid: 34400339
[44]	Winchester S, John S, Jabbar K, et al. Clinical efficacy of nitric oxide nasal spray (NONS) for the treatment of mild COVID-19 infection[J]. J Infect, 2021, 83(2):237-279. doi: 10.1016/j.jinf.2021.05.009 pmid: 33992687
[45]	Martel J, Ko YF, Young JD, et al. Could nasal nitric ox-ide help to mitigate the severity of COVID - 19?[J]. Mi-crobes Infect, 2020, 22(4-5):168-171.
[46]	ANON. Coronavirus disease 2019 (COVID-19) treatment guidelines[EB/OL]. Bethesda (MD): National Institutes of Health (US). 2021. https://www.ncbi.nlm.nih.gov/books/NBK570371/.
[47]	Ferrari M, Santini A, Protti A, et al. Inhaled nitric oxide in mechanically ventilated patients with COVID-19[J]. J Crit Care, 2020, 60:159-160. doi: S0883-9441(20)30651-1 pmid: 32814271
[48]	Abou-Arab O, Huette P, Debouvries F, et al. Inhaled ni-tric oxide for critically ill Covid-19 patients[J]. Crit Care, 2020, 24(1):645. doi: 10.1186/s13054-020-03371-x
[49]	Lotz C, Muellenbach RM, Meybohm P, et al. Effects of inhaled nitric oxide in COVID-19-induced ARDS — is it worthwhile?[J]. Acta Anaesthesiol Scand, 2021, 65(5):629-632. doi: 10.1111/aas.v65.5 URL
[50]	Robba C, Ball L, Battaglini D, et al. Early effects of venti-latory rescue therapies on systemic and cerebral oxygen-ation in mechanically ventilated COVID-19 patients with acute respiratory distress syndrome[J]. Crit Care, 2021, 25(1):111. doi: 10.1186/s13054-021-03537-1
[51]	Longobardo A, Montanari C, Shulman R, et al. Inhaled ni-tric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome[J]. Br J An-aesth, 2021, 126(1):e44-e46.
[52]	Di Fenza R, Shetty NS, Gianni S, et al. High - dose in-haled nitric oxide in acute hypoxemic respiratory failure due to COVID-19[J]. Am J Respir Crit Care Med, 2023, 208(12):1293-1304. doi: 10.1164/rccm.202304-0637OC URL
[53]	周永芳, 付江泉, 董文涛, 等. 吸入一氧化氮治疗重及危重型新型冠状病毒感染的疗效与安全性的 Meta 分析[J]. 结核与肺部疾病杂志, 2023, 4(1): 33-40.
[54]	Tavazzi G, Pozzi M, Mongodi S, et al. Inhaled nitric oxide in patients admitted to intensive care unit with COVID-19 pneumonia[J]. Crit Care, 2020, 24(1):508. doi: 10.1186/s13054-020-03222-9
[55]	Garfield B, McFadyen C, Briar C, et al. Potential for per-sonalised application of inhaled nitric oxide in COVID-19 pneumonia[J]. Br J Anaesth, 2021, 126(2):e72-e75.
[56]	Feng WX, Yang Y, Wen J, et al. Implication of inhaled nitric oxide for the treatment of critically ill COVID-19 patients with pulmonary hypertension[J]. ESC Heart Fail, 2021, 8(1):714-718. doi: 10.1002/ehf2.13023 pmid: 33205620
[57]	Vives M, Gascó I, Pla G, et al. Inhaled nitric oxide in acute severe pulmonary hypertension and severe acute re-spiratory distress syndrome secondary to COVID-19 pneumonia[J]. Am J Case Rep, 2022, 23:e937147.
[58]	Zamanian RT, Pollack CV Jr, Gentile MA, et al. Outpa-tient inhaled nitric oxide in a patient with vasoreactive id-iopathic pulmonary arterial hypertension and COVID-19 infection[J]. Am J Respir Crit Care Med, 2020, 202(1):130-132. doi: 10.1164/rccm.202004-0937LE URL
[59]	Zambrano LD, Ellington S, Strid P, et al. Update: charac-teristics of symptomatic women of reproductive age with laboratory - confirmed SARS - CoV - 2 infection by preg-nancy status - United States, January 22-October 3, 2020[J]. MMWR Morb Mortal Wkly Rep, 2020, 69(44):1641-1647. doi: 10.15585/mmwr.mm6944e3 URL
[60]	Kasehagen L, Byers P, Taylor K, et al. COVID-19-associ-ated deaths after SARS - CoV - 2 infection during preg-nancy - mississippi, March 1, 2020 - October 6, 2021[J]. MMWR Morb Mortal Wkly Rep, 2021, 70(47):1646-1648. doi: 10.15585/mmwr.mm7047e2 URL
[61]	Safaee FB, Wiegand SB, Pinciroli R, et al. High concen-trations of nitric oxide inhalation therapy in pregnant pa-tients with severe coronavirus disease 2019 (COVID-19)[J]. Obstet Gynecol, 2020, 136(6):1109-1113. doi: 10.1097/AOG.0000000000004128 URL
[62]	Valsecchi C, Winterton D, Safaee Fakhr B, et al. High-dose inhaled nitric oxide for the treatment of spontane-ously breathing pregnant patients with severe coronavirus disease 2019 (COVID-19) pneumonia[J]. Obstet Gynecol, 2022, 140(2):195-203. doi: 10.1097/AOG.0000000000004847 pmid: 35852269
[63]	Hedenstierna G, Chen L, Hedenstierna M, et al. Nitric ox-ide dosed in short bursts at high concentrations may pro-tect against COVID 19[J]. Nitric Oxide, 2020, 103:1-3. doi: S1089-8603(20)30161-0 pmid: 32590117
[64]	Gianni S, Fakhr BS, Morais CC A, et al. Nitric oxide gas inhalation to prevent COVID-2019 in healthcare provid-ers[J]. medRxiv, 2020:20054544.