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Tonight's FLARE will discuss the use of inhaled pulmonary vasodilators in ARDS, with a focus on the potential role of inhaled nitric oxide in COVID-19.


This piece is courtesy of Dr. Tiara Calhoun and Dr. Corey Hardin.
Summary points:
  • Inhaled pulmonary vasodilators (iNO, epoprostenol) are periodically used to improve oxygenation in ARDS.
  • Despite frequent use, inhaled pulmonary vasodilators have never been shown to improve outcomes.
  • There may be a role for these interventions when there is an emergent need to improve oxygenation.
  • There are postulated, but unproven, direct antiviral effects of iNO.
  • iNO may be preferable to other pulmonary vasodilators due to both direct antiviral effects and mode of delivery.
What is the evidence for inhaled nitric oxide (iNO) in ARDS?
Nitric oxide is a potent and rapid acting vasodilator. Nitric oxide gas, added to the patient’s inhaled gas mix, reaches only well-ventilated lung tissue, selectively dilating vessels associated with well-ventilated alveoli and thereby improving ventilation-perfusion matching (Griffiths and Evans, 2005).

iNO may result in a short term improvement in oxygenation but has not been shown to reduce morbidity or mortality. It has been associated with a risk of renal injury in a meta-analysis (Adhikari et al., 2014). For this reason, it is generally reserved for refractory hypoxemia on a case-by-case basis (Pipeling and Fan, 2010).

A 2016 Cochrane Systematic Review examining the effects of iNO in ARDS found no statistically significant effect of iNO on mortality (compared to placebo or standard of care, depending on the study) at 28 days or longest follow-up. There was a significant improvement in P/F ratio at 24 hours, but not at 48 or 72 hours in the iNO-treated groups. There were no statistically significant differences in ventilator‐free days, duration of mechanical ventilation, resolution of multi‐organ failure, quality of life, or length of stay in ICU or hospital. There was, however, a significant increase in renal failure in the iNO-treated groups (Gebistorf et al., 2016; Karam et al., 2017). There is little agreement on a putative mechanism to explain the association between nitric oxide and renal failure. In contrast to the statistical association demonstrated in the above studies, Lei et. al. actually demonstrated a reduction in renal failure post-cardiac surgery with the use of high-dose (80 ppm) iNO (Lei et al., 2018).
The O2 sat got better! Why does that not translate into a mortality benefit?
It seems intuitive that a therapy which improves oxygenation would improve outcomes. However, most patients with ARDS do not die of hypoxemia. Rather, they die of multi-organ failure, driven, at least in part, by poorly understood inflammatory processes, and not due to impairments in local oxygen delivery (see our March 25th FLARE on immunomodulation for a review). This may explain why randomized trials in unselected ARDS patients fail to demonstrate a mortality benefit in response to therapies targeted purely at improving oxygenation. That said, there is reason to believe that hypoxemia is a more important driver of mortality in primary respiratory infection such as COVID-19. In the 2009 H1N1 outbreak, respiratory failure was the cause of death in 43% of patients in one series (Rice et al., 2012). The relationship between any one physiologic variable and outcome in critical illness is not straight forward. Consider the factors that determine oxygen consumption (as described in the Fick equation):
VO2 = CO (CaO2 - CvO2) 
 
Where: VO2 is oxygen consumption, CO is cardiac output, CaO2 is arterial oxygen content and CvO2 is mixed venous oxygen content.
Improvements in O2 saturation contribute only to the CaO2 term (CaO2 = 1.34 x Hgb x SaO2). In the setting of limitations on CaO2, VO2 is maintained by increased tissue extraction (which lowers CvO2). Many patients with ARDS and sepsis, however, have preserved CvO2 (or, equivalently, central venous oxygen saturation). It follows that global oxygen delivery is not always the primary problem. There can be impaired delivery at the local tissue level (heterogeneity of perfusion, in situ clot, etc.) or impaired oxygen utilization (mitochondrial dysfunction, ‘cytopathic hypoxia’, shunt in tissue vascular beds, etc.). It is reasonable to hypothesize that some patients with respiratory failure do primarily have a deficit of oxygen delivery that can be remedied by improving the arterial oxygen saturation. Some, however, will not. This heterogeneity no doubt contributes to the conflicting evidence on the effects of iNO and is one reason why standard protocols stress reserving it for use as a rescue therapy in cases of refractory hypoxemia.
Could iNO have a role in COVID-19 ARDS?
A pilot study of 14 critically ill patients (treatment group=6; control group=8) treated with iNO in Beijing during the 2002-2003 SARS epidemic showed that low dose (up to 30 ppm, typical maximum 80 ppm) iNO for 3 to 7 days was associated with improved arterial oxygenation and decreased duration of ventilatory support (Chen et al., 2004). Improvement in secondary outcomes such as oxygenation is consistent with prior results in the ARDS literature (Adhikari et al., 2007, 2014; Gebistorf et al., 2016).

In addition to its role in vascular endothelial relaxation (and thereby pulmonary vasodilation), NO production has been reported to facilitate microbial- and tumor-killing activity in macrophages activated by lipopolysaccharide and interferon-γ (Hibbs et al., 1987; Stuehr et al., 1989; Uehara et al., 2015). Subsequent studies have demonstrated in vitro antimicrobial activity against a wide range of viruses, including SARS-CoV in eukaryotic cell models developed after the 2002-2003 epidemic (Akerström et al., 2005; Keyaerts et al., 2004). 

Based on the genetic similarities between SARS-CoV and SARS-CoV-2, it is hypothesized, but not yet demonstrated, that iNO may have an in vivo antiviral activity. This hypothesis has motivated a number of current clinical trials, which will examine the effect of iNO on both mortality from COVID-19 and on clearance of the SARS-CoV-2 virus.
So when do I use iNO and other pulmonary vasodilators?
iNO should be reserved as rescue therapy for persistent hypoxemia (SaO2 < 90%, PaO2 < 60 mmHg) unresponsive to PEEP titration and prone ventilation. There is some practice variation among institutions around the particular choice of inhaled pulmonary vasodilator. Alternatives to iNO traditionally include nebulized epoprostenol. As a nebulized agent, epoprostenol requires an inline filter which must be changed every 4 hours. This increases the number of times the ventilator circuit must be opened, thus potentially increasing risk to staff. For that reason, the MGH protocols prefer the use of iNO as a rescue pulmonary vasodilator.
FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine at Massachusetts General Hospital. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

Prior FLAREs can be found here, under "Fast Literature Updates".
Thank you for everything you are doing!
 - MGH FLARE
Interested in hearing more about a specific SARS-CoV-2 topic? Let us know via email. Interested in hearing more about a specific SARS-CoV-2 topic? Let us know via email.
References:
  • Adhikari, N.K.J., Burns, K.E.A., Friedrich, J.O., Granton, J.T., Cook, D.J., and Meade, M.O. (2007). Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 334, 779.
  • Adhikari, N.K.J., Dellinger, R.P., Lundin, S., Payen, D., Vallet, B., Gerlach, H., Park, K.J., Mehta, S., Slutsky, A.S., and Friedrich, J.O. (2014). Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit. Care Med. 42, 404–412.
  • Akerström, S., Mousavi-Jazi, M., Klingström, J., Leijon, M., Lundkvist, A., and Mirazimi, A. (2005). Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J. Virol. 79, 1966–1969.
  • Chen, L., Liu, P., Gao, H., Sun, B., Chao, D., Wang, F., Zhu, Y., Hedenstierna, G., and Wang, C.G. (2004). Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin. Infect. Dis. 39, 1531–1535.
  • Gebistorf, F., Karam, O., Wetterslev, J., and Afshari, A. (2016). Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst. Rev. CD002787.
  • Griffiths, M.J.D., and Evans, T.W. (2005). Inhaled nitric oxide therapy in adults. N. Engl. J. Med. 353, 2683–2695.
  • Hibbs, J.B., Jr, Taintor, R.R., and Vavrin, Z. (1987). Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235, 473–476.
  • Karam, O., Gebistorf, F., Wetterslev, J., and Afshari, A. (2017). The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis. Anaesthesia 72, 106–117.
  • Keyaerts, E., Vijgen, L., Chen, L., Maes, P., Hedenstierna, G., and Van Ranst, M. (2004). Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound. Int. J. Infect. Dis. 8, 223–226.
  • Lei, C., Berra, L., Rezoagli, E., Yu, B., Dong, H., Yu, S., Hou, L., Chen, M., Chen, W., Wang, H., et al. (2018). Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery. Am. J. Respir. Crit. Care Med. 198, 1279–1287.
  • Pipeling, M.R., and Fan, E. (2010). Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA 304, 2521–2527.
  • Rice, T.W., Rubinson, L., Uyeki, T.M., Vaughn, F.L., John, B.B., Miller, R.R., 3rd, Higgs, E., Randolph, A.G., Smoot, B.E., Thompson, B.T., et al. (2012). Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States. Crit. Care Med. 40, 1487–1498.
  • Stuehr, D.J., Gross, S.S., Sakuma, I., Levi, R., and Nathan, C.F. (1989). Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J. Exp. Med. 169, 1011–1020.
  • Uehara, E.U., Shida, B. de S., and de Brito, C.A. (2015). Role of nitric oxide in immune responses against viruses: beyond microbicidal activity. Inflamm. Res. 64, 845–852.






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