key: cord-289553-gygvhzcc
authors: Alvarez, Roger A.; Berra, Lorenzo; Gladwin, Mark T.
title: Home Nitric Oxide Therapy for COVID-19
date: 2020-07-01
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202005-1906ed
sha: 
doc_id: 289553
cord_uid: gygvhzcc

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It is with this backdrop that, in this issue of the Journal, Zamanian and colleagues (pp. 130-132) present an interesting and compelling case of a patient with pulmonary arterial hypertension (PAH) who was treated remotely in an ambulatory setting with inhaled nitric oxide (iNO) (5) . This patient with well-controlled vasoreactive PAH lived in a remote area more than 300 miles away from their center and experienced symptoms of worsening breathlessness after being diagnosed with COVID-19. Considering her concerns about traveling the long distance to their center to receive care, and with recognition of her prior confirmed responsiveness to iNO, they established a plan to support her with an ambulatory iNO system while monitoring her symptoms, vital signs, and functional capacity remotely. The patient had rapid and sustained improvement in her 6-minute-walk distance, as assessed by her caregiver, and symptom score, and she recovered over several days without having to engage emergency department or hospital care. This case report raises many questions. How might iNO have benefited this patient? Would we expect the benefit to be unique to iNO, or could other therapies that increase signaling along the NO axis also be helpful, such as NO donors, NO precursors, or phosphodiesterase 5 inhibitors? Can NO be safely administered to a patient in their own home, potentially helping to unburden overwhelmed healthcare systems?

NO is a free radial gas that functions as an important signaling molecule in human physiology. Its canonical receptor, guanylate cyclase, is highly expressed vascular smooth muscle cells, where it becomes activated once NO binds to its heme moiety, significantly increasing its enzymatic conversion of guanosine-59-triphosphate to cyclic guanosine monophosphate, which subsequently promotes vasorelaxation. As a gas, it has unique pharmacological properties including its delivery into well-ventilated lung units where it promotes local vasodilatation. When NO enters the blood stream, Table 1 . matching, increasing oxygenation (6) . NO also induces mild bronchodilation, and inhibits neutrophil-mediated oxidative burst (6) . These properties have been well known for decades and have led to U.S. Food and Drug Administration approval for the treatment of persistent pulmonary hypertension of the newborn, as well as various trials of iNO for patients with myriad conditions including ARDS, right ventricular failure after cardiac surgery, acute pulmonary embolism, and more recently pulmonary fibrosis in patients requiring long-term oxygen therapy (6) (7) (8) (9) (10) . In patients with SARS, iNO was associated with improvements in oxygenation in a severity-matched observational cohort (11) . Both endogenous and exogenous NO were shown to inhibit SARS-CoV viral replication (12) . While iNO has not been shown to reduce the time on mechanical ventilation or mortality in adults with ARDS, iNO does significantly improve oxygenation in ARDS patients and leads to reduction in pulmonary vascular resistance (6) (Figure 1 ). These therapeutic responses suggest that iNO could be used early in the course of COVID-19 infection to reduce the need for invasive mechanical ventilation. Studies of prone positioning and neuromuscular blockers in ARDS both provide a historical reminder of that potential, as clinical trials of early delivery of those therapies demonstrated benefits where prior studies had not (13, 14) .

Zamanian's case also highlights the feasibility of portable iNO delivery systems to treat patients at home, an option not previously available. While GENOSYL DS (VERO Biotech) is designed for the hospital intensive care setting, it has features, such as a tankless delivery system, that make it feasible to deliver at home, as demonstrated in this case. Other systems, such as INOpulse (Bellerophon Therapeutics), Nu-Med Plus (UT), and an iridium electric NO generator (Third Pole Therapeutics), have been designed with at least some degree of portability. Although there would be concerns in treating patients with a therapy like iNO at home, there is precedent. In a randomized and placebo-controlled trial of ambulatory patients with fibrotic lung disease requiring long-term oxygen, INOpulse therapy was associated with greater physical activity than placebo, and in an acute dose escalation study of patients with pulmonary hypertension associated with pulmonary fibrosis, iNO delivered through the INOpulse system lead to a 30% reduction in pulmonary vascular resistance, with improvements in Q _ and pulmonary artery compliance (15) . It is important to recognize that the experience of Dr. Zamanian's patient is unlikely to be representative of all patients with COVID-19, or even those with PAH complicated by COVID-19. This patient had an established diagnosis of vasoreactive PAH, and as a physician herself, was uniquely qualified to engage in a complex treatment regimen. But the example serves as an interesting proof-of-concept study that supports the rationale of studying iNO therapy in patients with COVID-19 to establish if this intervention can improve oxygenation and reduce need for mechanical ventilation. In Table 1 , we have summarized planned and ongoing clinical trials available that are testing NO gas therapy in COVID-19 patients. Dr. Zamanian and colleagues are to be commended for their innovative approach and important contribution to this field. n Outpatient therapy of pulmonary embolism (PE) has gained greater acceptance in the current era of risk stratification and direct oral anticoagulant (DOAC)-based treatment regimens. A growing experience in the medical literature has documented the safety and improved patient satisfaction with outpatient treatment of low-risk PE (1) (2) (3) (4) . Furthermore, the opportunity to decongest emergency departments and inpatient units, and reduce the overall cost burden of PE on healthcare systems, compels clinicians to select this strategy when feasible (5) . The 2019 European Society of Cardiology guidelines for diagnosis and management of acute PE recommend risk stratification to identify low-risk patients who may be considered for home treatment if outpatient care can be arranged and adequate anticoagulation initiated (6) . The 2016 American College of Chest Physicians guidelines suggest early discharge or home treatment of PE over hospitalization in low-risk patients whose home circumstances are adequate (7) . However, despite tools for identification of appropriate patients, options for safe and effective outpatient treatment, and endorsement by guidelines, patients with low-risk PE are still frequently hospitalized (4) .

Current risk stratification strategies for acute PE rely on synthesis of clinical decision rules; cardiac biomarkers, such as troponin and BNP (brain-type natriuretic peptide); and imaging of right ventricular (RV) function (8) . Although these tools have been most widely endorsed for prognostication of adverse outcomes, they are also used for identification of low-risk patients who may avoid hospitalization for acute PE. Specific criteria for eligibility for home therapy were assessed by the Hestia investigators in a prospective cohort study of 297 patients with PE (9). The Hestia criteria identified a cohort of patients with acute PE who completed outpatient therapy with a low risk of adverse events, including recurrent venous thromboembolism (2%), all-cause mortality (1%), and major bleeding (0.7%).

Further contributing to a low adverse event rate with outpatient therapy for acute PE is the widespread integration of DOACs into treatment algorithms. Compared with vitamin K antagonists, DOACs provide similar efficacy but enhanced safety with a 40% reduction in major bleeding and 60% reduction in intracranial hemorrhage (10) . The relative ease with which the DOACs are initiated and the promise of consistent, safe, and effective anticoagulation without the need for dose adjustment make them preferred for PE treatment and a major advance in the movement toward outpatient therapy (6, 7) .

In this issue of the Journal, Hendriks and colleagues (pp. 138-141) provide an important perspective on risk stratification in patients with PE who are eligible for outpatient therapy (11) . The investigators report a post hoc analysis of combined data from the prospective Hestia and Vesta studies to assess the incremental prognostic value of increased computed tomographic-measured right ventricular-to-left ventricular (RV-to-LV) diameter ratio on recurrent venous thromboembolism and mortality. In the analysis of 752 patients with PE treated at home, 30% had RV enlargement (RV-to-LV diameter ratio . 1). Adverse events were infrequent in these otherwise low-risk patients with RV enlargement compared with those without (2.7% vs. 2.3%; odds ratio, 1.2; 95% confidence interval, 0.44-3.2). The investigators concluded that RV enlargement would have excluded a large proportion of their cohort from outpatient therapy without impacting prognosis.

Despite the main limitation of its post hoc design, the study findings support previous observations demonstrating that routine assessment of RV function and cardiac biomarkers in low-risk patients identified using clinical criteria provides little prognostic value and may come at the cost of hospitalizing patients who could otherwise be treated at home (Table 1) . A previous analysis from the study investigators demonstrated that 35% of patients who were treated at home according to the Hestia criteria had RV dysfunction and were classified as intermediate risk according to the European Society of Cardiology criteria (12) . Similarly, other studies from the investigators have shown that increased high-sensitivity cardiac troponin T (13) and N-terminal pro-BNP (14) were associated with a low rate of adverse events in patients with PE determined to be low-risk by the Hestia criteria. One potential explanation for infrequent adverse events in clinically 

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Copyright © 2020 by the American Thoracic Society Listen to Your Heart (but DON'T Look at Theirs): Risk Assessment for Home Treatment of Pulmonary Embolism