|Year : 2021 | Volume
| Issue : 3 | Page : 236-243
Efficacy and safety of inhaled nitric oxide in the treatment of severe/critical COVID-19 patients: A systematic review
Ajay Prakash1, Sukhmeet Kaur1, Charanjeet Kaur1, Praisy K Prabha1, Anusuya Bhatacharya2, Phulen Sarma1, Bikash Medhi1
1 Department of Pharmacology, Experimental Pharmacology Laboratory, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Ophthalmology, GMCH, Chandigarh, India
|Date of Submission||31-May-2021|
|Date of Decision||05-Jun-2021|
|Date of Acceptance||08-Jun-2021|
|Date of Web Publication||22-Jun-2021|
Prof. Bikash Medhi
Research Block B, 4th Floor, Room No. 4043, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
OBJECTIVE: Present systematic review aimed to analyze the effect of inhaled nitric oxide (iNO) in the treatment of severe COVID-19 and to compare it to standard of care (SOC), antiviral medications, and other medicines.
MATERIALS AND METHODS: Medline (PubMed), Scopus, Embase, Ovid, Web of Science, Science Direct, Wiley Online Library, BioRxiv and MedRxiv, and Cochrane (up to April 20, 2021) were the search databases. Two reviewers (SK and CK) independently selected the electronic published literature that studied the effect of nitric oxide with SOC or control. The clinical and physiological outcomes such as prevention of progressive systemic de-oxygenation/clinical improvement, mortality, duration of mechanical ventilation, improvement in pulmonary arterial pressure, and adverse events were assessed.
RESULTS: The 14 retrospective/protective studies randomly assigning 423 patients met the inclusion criteria. Cumulative study of the selected articles showed that iNO has a mild impact on ventilation time or ventilator-free days. iNO has increased the partial pressure of oxygen/fraction of inspired oxygen ratio of fraction of inspired oxygen in a few patients as compared to baseline. However, in most of the studies, it does not have better outcome when compared to the baseline improvement.
CONCLUSIONS: In patients with COVID-19 with acute respiratory distress syndrome, nitric oxide is linked to a slight increase in oxygenation but has no effect on mortality.
Keywords: Coronavirus, COVID-19, inhaled nitric oxide, nitric oxide, oxygenation, ventilation
|How to cite this article:|
Prakash A, Kaur S, Kaur C, Prabha PK, Bhatacharya A, Sarma P, Medhi B. Efficacy and safety of inhaled nitric oxide in the treatment of severe/critical COVID-19 patients: A systematic review. Indian J Pharmacol 2021;53:236-43
|How to cite this URL:|
Prakash A, Kaur S, Kaur C, Prabha PK, Bhatacharya A, Sarma P, Medhi B. Efficacy and safety of inhaled nitric oxide in the treatment of severe/critical COVID-19 patients: A systematic review. Indian J Pharmacol [serial online] 2021 [cited 2022 Aug 8];53:236-43. Available from: https://www.ijp-online.com/text.asp?2021/53/3/236/318971
| » Introduction|| |
COVID-19 has developed as a global challenge to the global health system and its stakeholders as its first and second waves continue to spread. As of May 11, 2021, there were 159,699,271 COVID-19 cases recorded worldwide, with 137,399,547 (86.04%) recovered and 3,319,919 (2.08%) deaths. Acute respiratory distress syndrome (ARDS) is the main characteristic of COVID-19–positive patients which identified by pulmonary hypertension and increased intrapulmonary shunting of blood through hypoventilated regions. As pandemic spreading rapidly, we need fast and accurate treatment for COVID 19, which is essential to limit the further spread of the virus or there must be some agent which fulfill the demand of oxygenation in the case of severe hypoxia, the major cause of death. Currently, there are no specific antiviral therapies for COVID-19 available for human use. COVID-19 is primarily managed by mechanical ventilation with antiviral therapy and steroids in the severe cases.,
Inhaled nitric oxide (iNO) is a gaseous free radical which is produced from arginine with the help of enzymes (neuronal, endothelial, and inducible nitric oxide synthase) that controls vasodilation. The iNO plays a specific role in maintaining the vascular system and has the unique capability to produce pulmonary vasodilation by involving in the pathological and physiological process, which includes relaxation of smooth muscle cells, immune response, and antimicrobial activities to increase the blood flow.,, US FDA approved iNO for the probable treatment in the emergency of hypoxic respiratory failure to the neonates/pediatric population and fulfill immediate requirement of extracorporeal membrane oxygenation, whereas iNO is already being used for a wide range of cardiopulmonary conditions. It is a well-known neurotransmitter, vasodilator, coagulation mediator, antimicrobial agent, or SARS-CoV replication inhibitor.,
The ARDS has different clinical presentations in COVID-19 and non-COVID-19 patients; higher rate of endothelial damage (vascular) and microthrombi (pulmonary) was seen in ARDS with nCoV-2019–infected patient as compared to the non-COVID-19 patients., Longobardo et al., 2020 explored the hypothesis of an increase in partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio after therapy with iNO in patients with ARDS not caused by COVID-19. Literature showed that in well-ventilated lung tissue, iNO only dilates the pulmonary arteries with no effect on breath perfusion, but it can decrease intrapulmonary shunt and can increase arterial oxygenation throughout the body.,,,, There are several studies registered at www. clinicaltrial.gov, which suggests the importance of the intervention in COVID-19 [Table 1]. Therefore, the present systematic review aimed to establish the efficacy and safety of iNO in the treatment of nCoV-2019–infected patients.
|Table 1: Summary of the clinical studies registered in “clinicaltrial-gov” for inhaled nitric oxide in the treatment of COVID-19|
Click here to view
| » Materials and Methods|| |
The systematic review aimed to establish the efficacy and safety as per following outcomes:
- Improvement in PaO2/FiO2 ratio
- Need of mechanical ventilation and frequency of intubation
- Length of hospital stay
- Change of level of IL-6, TNF-α, fibrinogen, C-reactive protein (CRP), ferritin, and dimer after iNO
Database search and data extraction
The data was screened at 11 medical literature databases (PubMed, Cinahl Plus, Scopus, Embase, Ovid, Web of Science, Science Direct, Wiley online library, BioRxiv and MedRxiv, and Cochrane) performed up to April 20, 2021, without any language restriction. Apart from these, the references of the included studies were also screened for possible inclusion criteria. The search was conducted using the keywords: “((COVID-19 OR NO” OR “SARS coronavirus-2” OR COVID or SARS)) AND ((”Nitric oxide OR “NO” or “iNO” or “inhaled nitric oxide OR inhalational NO”) AND “nCoV”).
Screening of articles
After searching the databases with appropriate keywords, duplicates were removed, and three reviewers (SK, PKP, and YS) screened the studies using title and abstract as predefined inclusion/exclusion criteria. Full text of relevant studies was further evaluated for possible inclusion in the systematic review using inclusion/exclusion criteria. Any discrepancies among investigators were resolved by consulting with BM and AP.
The studies were included in the systematic review with any of the above-mentioned outcomes described in the article following iNO treatment in COVID-19–positive patients. There are no restrictions on geographical site selection; therefore, any location studies, whether open level/retrospective or prospective or cross-sectional, will be included in the study.
However, articles not related to the treatment of iNO or have iNO efficacy in other disease from COVID-19 or not an original article/report, review letter, or full text with no outcome as described were excluded from the study.
| » Results and Discussion|| |
Study (data) selection
Data were extracted by three reviewers (HS, CK, and PKP) independently extracted from the included articles using a pretested data extraction form. After screening of 11 medical literature databases (PubMed, Cinahl Plus, Scopus, Embase, Ovid, Web of Science, Science Direct, Wiley online library, BioRxiv and MedRxiv, and Cochrane) till 20 April 2021 without any language restriction, 369 studies were selected, of which 172 from PubMed and 221 from other sources. The studies were screened based on inclusion and exclusion criteria. Finally, 14 retrospective/prospective studies were selected with the 423 patients with COVID-19–positive patients treated with iNO [Figure 1].
Improvement in partial pressure of oxygen/fraction of inspired oxygen ratio
In the 24 h after starting iNO, Longobardo et al., 2020 observed that the COVID-19 group had more males with ARDS and that there were no changes between groups in mode of mean airway pressure, ventilation, volume (tidal), positive end-expiratory pressures (PEEP), fluid balance, or use of other drugs. However, iNO treatment improved PaO2/FiO2 ratio significantly less than in COVID-19–associated ARDS patients compared to ARDS patients who were not associated to COVID-19 (3% vs. 47%) [Table 2], while Bagate et al., 2020 indicated that a combination of iNO and almitrine improved blood oxygenation by more than 50% in severe COVID-19 patients as compared to the iNO-alone group. They observed that the improvement in the ratio of PaO2/FiO2 was significantly better, i.e., 102–180 mmHg when treated with combination of iNO and almitrine [Table 2].
|Table 2: Summary of the clinical studies included in the systematic review|
Click here to view
The findings of another study by Michael et al., 2020 which found no significant difference between individuals who tested at 10 and 20 ppm of iNO and found a median rise in PaO2/FiO2 ratio of 2.2% (95% confidence interval [CI]: 1.3–12) (from 88 [range: 73–110] to 94 [range: 74–116]) were similar. In another study, 10 COVID-19–positive patients had their mean iNO and PaO2 increased from 62 ± 9 to 64 ± 14 mmHg (P = 0.427) and their mean PaO2/FiO2 raised from 81 ± 19 to 84 ± 22 mmHg (P = 0.325), both of which were not significantly different from baseline, while their mean mechanical ventilation duration was 34 ± 21 days. The study by Moni et al., 2021 demonstrated that iNO treatment raised cycle threshold (Ct) value to normalize to 8.5 or more within 5 days in all patients, whereas viral load was cleared in 72% of patients in the control group (P = 0.04). The same pattern was found by Abou-Arab et al., 2020 who studied between two groups, i.e. iNO responders versus nonresponders. PaO2/FiO2 was considerably lower in the responders' group compared to the nonresponders' group (70 [63–100] vs. 134 [83–173]; P = 0.0001) but was consistent following iNO delivery (P = 0.068). At baseline and after iNO delivery, PaCO2 levels were comparable between groups. They found a response rate of 65% after the treatment of iNO without practicing prone positioning. Feng et al., 2020 reported that iNO was significantly beneficial to reduce and stabilize the pulmonary artery systolic pressure and decrease the risk of right heart failure in the critically ill COVID-19 patients. They observed that the significant improvement of oxygenation in the COVID-19 patients based on the ratio of PaO2/FiO2 and as comparison to baseline. Lotz et al., 2021 showed beneficial effect of iNO in COVID 19–induced moderate to severe ARDS, by decreasing pulmonary vascular resistance with severe ARDS.
Need of mechanical ventilation
COVID-19 infection induces severe hypoxemia by decreasing ventilation-perfusion matching and increasing pulmonary vascular pressure. Therefore, during the management of COVID-19, maintaining ventilation and oxygenation is a main objective, and if it not maintained, we need mechanical ventilation invasive/noninvasive to fulfill the lung/body requirements. Study by Parikh et al., 2020 showed that requirements of mechanical ventilation (invasive) were significantly reduced when patients were treated by iNO, i.e., about 53.9% of patients did not require mechanical ventilation, whereas Bagate et al., 2020 showed that there is no improvement in the oxygenation in iNO treatment alone but got improved when iNO was given with the almitrine (iNO + almitrine). The similar trends have been finding in the study by Robba et al. 2021 which showed the significant improvement in rescue therapies and observed that iNO increased the level of PaO2 from 65 to 72 mmHg, i.e., the oxygenation level.,
Effect of inhaled nitric oxide in reducing cytokines, fibrinogen, C-reactive protein, ferritin, and dimer level!
There was very less studies found that studied the cytokines, fibrinogen, CRP, ferritin, and dimer level following iNO therapy as a primary or secondary objective. Parikh et al., 2020 reported that in 21 nonintubated patients, there is no improvement in CRP and ferritin level after iNO treatment, but the level of D-dimer was increased in 64.1% with a median change of 115 ng/ml (P = 0.0052), whereas Longobardo et al., 2020 observed that iNO respondents and nonrespondents have no major differences as compared to the baseline values of D-dimer levels, fluid balance, prone position ventilation and CRP.
In most of the screened article, authors have not mentioned about the mortality benefit in the iNO treatment groups. Ferrari et al., 2020 showed that there was 20% mortality, i.e., out of 10 patients, 8 patients (80%) were discharged, but the reason of 2 deaths were not mentioned in the article. In another article, Parikh et al., 2020 showed only 1 death out of 21 patients, i.e., 4.76% mortality, was seen and the rest successfully discharged.
Limitation of the study
The current systematic review is carried out to interpret the effect of iNO in the COVID-19 patients. Whether administration of iNO improved the outcome/oxygenation status (PaO2/FiO2 ratio) to the patients or not or have the better safety profile. Currently, we find that extremely limited number of retrospective/prospective studies were published and lacks randomized clinical trials (RCTs) to ensure the quality of data. As per the current search and analysis, we find that there are specific endpoints/outcomes defined such as improvement in PaO2/FiO2 ratio, prevention of progression assessed by an alternate severity scale, length of hospital Stay (death assigned as worst case), need of ventilation and frequency of intubation, effectiveness in reducing cytokines level (IL6/IL10), TNF-alpha, fibrinogen, CRP, ferritin, and dimer levels and finally the morbidity and mortality. There is no concurrent finding in all the selected articles and data found in these articles are sparse and incomplete. However, during the search of articles, we find that the there are many RCTs are registered with “clinicaltrial.gov,”E which in future their result may give us some confirmatory outcome regarding the use of iNO in the COVID-19 patients [Table 1].
| » Conclusion|| |
In the present systematic review, there is no persistent finding among the studies published. However, few studies have reported its moderate activity in elevating the level of PaO2/FiO2 ratio from its baseline, but there is no effect have been seen in the comparative study with almitrine or alone.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ignarro LJ. Inhaled NO and COVID-19. Br J Pharmacol 2020;177:3848-9.
Raju R, Prajith V, Biatris PS, Sam Johnson UC. Therapeutic role of corticosteroids in COVID-19: A systematic review of registered clinical trials. Futur J Pharm Sci 2021;7:67.
Adusumilli NC, Zhang D, Friedman JM, Friedman AJ. Harnessing nitric oxide for preventing, limiting and treating the severe pulmonary consequences of COVID-19. Nitric Oxide 2020;103:4-8.
Ferrari M, Santini A, Protti A, Andreis DT, Iapichino G, Castellani G, et al.
Inhaled nitric oxide in mechanically ventilated patients with COVID-19. J Crit Care 2020;60:159-60.
Bagate F, Tuffet S, Masi P, Perier F, Razazi K, de Prost N, et al.
Rescue therapy with inhaled nitric oxide and almitrine in COVID-19 patients with severe acute respiratory distress syndrome. Ann Intensive Care 2020;10:1-7.
Sokol GM, Konduri GG, Van Meurs KP. Inhaled nitric oxide therapy for pulmonary disorders of the term and preterm infant. Semin Perinatol 2016;40:356-69.
Kida K, Shirozu K, Yu B, Mandeville JB, Bloch KD, Ichinose F. Beneficial effects of nitric oxide on outcomes after cardiac arrest and cardiopulmonary resuscitation in hypothermia-treated mice. Anesthesiology 2014;120:880-9.
Morgan RW, Sutton RM, Himebauch AS, Roberts AL, Landis WP, Lin Y, et al
. A randomized and blinded trial of inhaled nitric oxide in a piglet model of pediatric cardiopulmonary resuscitation. Resuscitation 2021;162:274-83.
Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al.
High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study. Intensive Care Med 2020;46:1089-98.
Menter T, Haslbauer JD, Nienhold R, Savic S, Hopfer H, Deigendesch N, et al.
Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 2020;77:198-209.
Longobardo A, Montanari C, Shulman R, Benhalim S, Singer M, Arulkumaran N. Inhaled nitric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome. Br J Anaesth 2021;126:e44-6.
Feng WX, Yang Y, Wen J, Liu YX, Liu L, Feng C. Implication of inhaled nitric oxide for the treatment of critically ill COVID-19 patients with pulmonary hypertension. ESC Heart Fail 2021;8:714-8.
Yu B, Ichinose F, Bloch DB, Zapol WM. Inhaled nitric oxide. Br J Pharmacol 2019;176:246-55.
Albert M, Corsilli D, Williamson DR, Brosseau M, Bellemare P, Delisle S, et al.
Comparison of inhaled milrinone, nitric oxide and prostacyclin in acute respiratory distress syndrome. World J Crit Care Med 2017;6:74-8.
Umakanthan S, Sahu P, Ranade AV, Bukelo MM, Rao JS, Abrahao-Machado LF, et al.
Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Postgrad Med J 2020;96:753-8.
Ricciardolo FL, Bertolini F, Carriero V, Högman M. Nitric oxide's physiologic effects and potential as a therapeutic agent against COVID-19. J Breath Res 2020;15:014001.
Parikh R, Wilson C, Weinberg J, Gavin D, Murphy J, Reardon CC. Inhaled nitric oxide treatment in spontaneously breathing COVID-19 patients. Ther Adv Respir Dis 2020;14:1753466620933510.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
Bagate F, Tuffet S, Masi P, Perier F, Razazi K, de Prost N, et al.
Rescue therapy with inhaled nitric oxide and almitrine in COVID-19 patients with severe acute respiratory distress syndrome. Ann Intensive Care 2020;10:151.
Cardinale M, Esnault P, Cotte J, Cungi PJ, Goutorbe P. Effect of almitrine bismesylate and inhaled nitric oxide on oxygenation in COVID-19 acute respiratory distress syndrome. Anaesth Crit Care Pain Med 2020;39:471-2.
Moni M, Madathil T, Sathyapalan DT, Menon V, Gutjahr G, Edathadathil F, et al
. A feasibility trial to evaluate the composite efficacy of inhaled nitric oxide in the treatment of COVID 19 pneumonia: Impact on viral load and clinical outcomes. medRxiv 2021.04.15.21255300; doi: https://doi.org/10.1101/2021.04.15.21255300
Abou-Arab O, Huette P, Debouvries F, Dupont H, Jounieaux V, Mahjoub Y. Inhaled nitric oxide for critically ill Covid-19 patients: a prospective study. Crit Care 2020;24:645.
Lotz C, Muellenbach RM, Meybohm P, Mutlak H, Lepper PM, Rolfes CB, et al
. Effects of inhaled nitric oxide in COVID-19–induced ARDS – Is it worthwhile? Acta Anaesthesiol Scand 2021;65:629-32.
Robba C, Ball L, Battaglini D, Cardim D, Moncalvo E, Brunetti I, et al.
Early effects of ventilatory rescue therapies on systemic and cerebral oxygenation in mechanically ventilated COVID-19 patients with acute respiratory distress syndrome: A prospective observational study. Crit Care 2021;25:1-3.
Safaee Fakhr B, Wiegand SB, Pinciroli R, Gianni S, Morais CC, Ikeda T, et al.
High concentrations of nitric oxide inhalation therapy in pregnant patients with severe coronavirus disease 2019 (COVID-19). Obstet Gynecol 2020;136:1109-13.
Shekar K, Varkey S, Cornmell G, Parsons L, Tol M, Siuba M, et al
. Feasibility of non invasive nitric oxide inhalation in acute hypoxemic respiratory failure: Potential role during the COVID 19 pandemic. medRxiv 2020.05.17.20082123; doi: https://doi.org/10.1101/2020.05.17.20082123
Caplan M, Goutay J, Bignon A, Jaillette E, Favory R, Mathieu D, et al.
Almitrine infusion in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome: A single-center observational study. Crit Care Med 2021;49:e191-8.
Tavazzi G, Pozzi M, Mongodi S, Dammassa V, Romito G, Mojoli F. Inhaled nitric oxide in patients admitted to intensive care unit with COVID-19 pneumonia. Crit Care 2020;24:508.
[Table 1], [Table 2]