key: cord-0293273-0pdkbd59
authors: Giri, A. R.; Yarrarapu, S. N. S.; Kaur, N.; Hochwald, A. P.; Crook, J.; Helgeson, S.; Harrison, M. F.; Patel, N.; Guru, P. K.; Lowman, P.; Moreno-Franco, P.; Lee, A.; Sanghavi, D. K.
title: Inhaled nitric oxide use in COVID19-induced hypoxemic respiratory failure.
date: 2021-08-21
journal: nan
DOI: 10.1101/2021.08.19.21262314
sha: 1d5e6b97ff2186b54b11ebb8356a44063564b51b
doc_id: 293273
cord_uid: 0pdkbd59

Introduction: Nitric Oxide (NO) is an endogenous vasodilator that is synthesized by the vascular endothelium. Due to its vasodilatory effect and short half-life, the use of NO as an exogenous inhaled medication (iNO) to target the pulmonary vasculature, in conditions with increased pulmonary vascular resistance, has been studied. The use of iNO in patients with ARDS secondary to COVID-19 has therapeutic importance in improving oxygenation. It also has potential anti-viral, anti-inflammatory, and anti-thrombotic properties. Herein, we want to share our experience of use of iNO in hypoxemic respiratory failure secondary to COVID 19 pneumonia. We hypothesized that iNO may be beneficial at preventing intubation, decreasing invasive mechanical ventilation duration, and consequently improve outcomes including hospital mortality. Methods: This is a descriptive hypothesis generating study of patients admitted for COVID-19 pneumonia who received iNO for hypoxemic respiratory failure, at a single tertiary care center. We collected information on patient demographics, co-morbidities, iNO treatment, need for intubation, arterial blood gas analysis, laboratory values, hospital length of stay, and mortality. Patients were divided into two groups based on the timing of iNO administration: group 1 - pre-intubation (i.e. iNO started at least 1 day prior to endotracheal intubation, if any) and group 2 - post-intubation (i.e. iNO started on the same day as or after endotracheal intubation and mechanical ventilation). Result: A total of 45 (group 1, n=26 [57.8%] vs group2, n=19 [42.2%]) COVID 19 patients who had iNO use. The mean time from hospital admission to iNO administration(days) in group 1 was 2.1 (1.8, SD) vs 4.2 (5.9, SD) in group 2. The mean hospital length of stay from the beginning of iNO treatment until discharge or death was 18.3 vs 26.2 days, with 8 deaths (30.8%) vs 9 deaths (47.4%) in group 1 vs group 2, respectively. Discussion: Our study is unable to demonstrate comparably outcomes benefit of iNO. Although there was a trend towards decreased need for invasive mechanical ventilation in group 1[Only 11 (42.3 %) patients were intubated out of 26 who received iNO early after hospital admission (2.3 days)], no statistical significance could be achieved because of small sample size. Our study demonstrated that iNO administration pre-intubation did not appear harmful and appears to be safe, complementary to HFNC, signalling the domain where systematic investigation is required to confirm or not the potential for iNO to improve patient outcomes in the management of COVID 19-induced hypoxemic respiratory failure. Conclusion: This study showcases the potential benefit of early pre-intubation use of iNO in COVID patients with hypoxemic respiratory failure. This study could conclusively form the basis for a prospective trial and could have a tremendous impact in improving patient outcomes.

Methods: This is a descriptive hypothesis generating study of patients admitted for COVID-19 pneumonia who received iNO for hypoxemic respiratory failure, at a single tertiary care center. We collected information on patient demographics, co-morbidities, iNO treatment, need for intubation, arterial blood gas analysis, laboratory values, hospital length of stay, and mortality. Patients were divided into two groups based on the timing of iNO administration: group 1 -"pre-intubation" (i.e. iNO started at least 1 day prior to endotracheal intubation, if any) and group 2 -"post-intubation" (i.e. iNO started on the same day as or after endotracheal intubation and mechanical ventilation). 

Our study is unable to demonstrate comparably outcomes benefit of iNO. Although there was a trend towards decreased need for invasive mechanical ventilation in group 1[Only 11 (42.3 %) patients were intubated out of 26 who received iNO early after hospital admission (2.3 days)], no statistical significance could be achieved because of small sample size.

Our study demonstrated that iNO administration pre-intubation did not appear harmful and appears to be safe, complementary to HFNC, signalling the domain where systematic investigation is required to confirm or not the potential for iNO to improve patient outcomes in the management of COVID 19-induced hypoxemic respiratory failure.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 21, 2021. ; https://doi.org/10.1101/2021.08.19.21262314 doi: medRxiv preprint

This study showcases the potential benefit of early pre-intubation use of iNO in COVID patients with hypoxemic respiratory failure. This study could conclusively form the basis for a prospective trial and could have a tremendous impact in improving patient outcomes.

Keywords: Inhaled nitric oxide; Acute respiratory distress syndrome; COVID 19; Critical care; Invasive mechanical ventilation Abbreviations: iNO (Inhaled nitric oxide); ICU (Intensive care unit); SOFA (Sequential Organ Failure Assessment); SD (Standard Deviation).

Introduction:

Nitric oxide (NO)is a potent vasodilator that is endogenously synthesized by the vascular endothelium. Due to its short half-life, inhaled NO(iNO) can provide vasodilation preferentially to ventilated areas improving ventilation-perfusion matching, in addition to potential benefits on pulmonary pressures and right heart afterload reduction. 1 In critically ill patients, management of acute respiratory distress syndrome (ARDS) is predominantly supportive and without specific definitive treatment. The use of iNO in ARDS been relegated to "rescue" or "bridging" therapy for refractory hypoxemia. Although clinical trials have not been able to demonstrate a survival benefit of iNO in ARDS, iNO was universally applied late in the course of hypoxic respiratory failure, specifically, after they had required invasive mechanical ventilation. Early during the COVID-19 pandemic, facing scarce . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 21, 2021. ; https://doi.org/10.1101/2021.08.19.21262314 doi: medRxiv preprint resources including mechanical ventilators and appropriately trained staff, our center initiated a treatment protocol of considering earlier use of iNO, pre-intubation, to manage refractory hypoxia and possibly delay need for endotracheal intubation or shorten duration of mechanical ventilator need. iNO has been shown to improve gas-exchange in a subset of patients affected by COVID-19 ARDS 2,3 , but it also has theoretical benefits in the specific context of COVID-19 pneumonia due to its anti-viral, anti-inflammatory, and anti-thrombotic properties. 1 Hence, we aimed to explore whether pre-intubation administration of iNO resulted in any improved clinical outcomes among patients with COVID-19induced hypoxic respiratory failure. Herein, we want to share our experience of use of iNO in hypoxemic respiratory failure secondary to COVID 19 pneumonia. We hypothesized that iNO may be beneficial at preventing intubation, decreasing invasive mechanical ventilation duration, and consequently improve outcomes including hospital mortality.

This is a descriptive hypothesis generating study of patients admitted during June 2020 to December 2020 with COVID-19 pneumonia who received iNO for hypoxemic respiratory failure, at a single tertiary care center. Criteria for iNO (5-20 ppm) addition to high flow nasal canula (HFNC) included patients with pure hypoxemia without increased work of breathing or respiratory acidosis, or if patient showed evidence of pulmonary hypertension (PH) and right ventricular (RV) failure. We collected information on patient demographics, co-morbidities, iNO treatment, need for intubation, arterial blood gas analysis, laboratory values, hospital length of stay, and mortality. Patients were divided into two groups based on the timing of iNO administration: group 1 -"pre-intubation" (i.e. iNO started at least 1 day prior to endotracheal intubation, if any) and group 2 -"post-intubation" (i.e. iNO started on the same day as or after . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 21, 2021. ; https://doi.org/10.1101/2021.08.19.21262314 doi: medRxiv preprint endotracheal intubation and mechanical ventilation).Moreover, we compared two groups who required invasive endotracheal intubation (group 1) versus those who did not require intubation (group 2) as shown in table 3. We further analysed data based on survival at discharge and divided cohort into two groups: group 1 -alive and group 2 -deceased (refer table 4). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

A

The copyright holder for this preprint this version posted August 21, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 21, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 21, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 21, 2021. Discussion:

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 21, 2021. ; https://doi.org/10.1101/2021.08.19.21262314 doi: medRxiv preprint

In this study, we have summarized the available data and underlined the hypoxemic respiratory failure scenario wherein iNO can be used. Although our study was unable to demonstrate comparably the outcomes of iNO use in either group, across the three different analyses of COVID-19 patients, there was a trend of decreased need for invasive mechanical ventilation in is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 21, 2021. ; https://doi.org/10.1101/2021.08.19.21262314 doi: medRxiv preprint iNO use. 6, 7 These studies investigated the use of iNO in COVID-19 with mixed results varying from positive outcomes to a lack of any effect, but did not address the effects of iNO use on intubation and subsequent invasive mechanical ventilator support. Our study demonstrated that iNO administration pre-intubation was not harmful and appears to be safe, complementary to HFNC, signalling the domain where systematic investigation is required to confirm the potential for iNO to improve patient outcomes in the management of COVID 19-induced hypoxemic respiratory failure.

This is retrospective study with small sample size; hence desired results were not statistically significant. The effects of iNO were not charted in terms of patient outcomes. We collected SOFA score on admission. Therefore, the severity of patient condition may have deteriorated or improved after 24 hrs. Potential confounders include the novel nature of this virus with rapidly changing standards of medical care, which are not included in this study.

This study showcases the potential benefit of early pre-intubation use of iNO in COVID-19 patients with hypoxemic respiratory failure. This study could conclusively form the basis for a prospective trial and could have a tremendous impact in improving patient outcomes. Thus, more studies are needed in future to evaluate the effects of iNO use in hypoxemic respiratory failure.

No conflicts of interest.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 21, 2021. ; https://doi.org/10.1101/2021.08.19.21262314 doi: medRxiv preprint

The role of NO in COVID-19 and potential therapeutic strategies

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Effects of inhaled nitric oxide in COVID-19-induced ARDS -Is it worthwhile?

Use of nasal high flow oxygen during acute respiratory failure

Nitric oxide inhalation as an interventional rescue therapy for COVID-19-induced acute respiratory distress syndrome

Inhaled nitric oxide in patients admitted to intensive care unit with COVID-19 pneumonia

Inhaled nitric oxide in mechanically ventilated patients with COVID-19