IntroductionThe respiratory compromise caused by COVID-19 pneumonia can be profound, and complicated by severe hypoxia, thromboembolic disease, and Acute Respiratory Distress Syndrome (ARDS). Treatment in the acute setting consists of respiratory support, corticosteroids, and anticoagulation. The pathogenesis of severe respiratory compromise in COVID-19 is at least partly related to thrombotic events in the pulmonary microvasculature (1Carfora V Spiniello G Ricciolino R Di Mauro M Migliaccio MG Mottola FF et al.Anticoagulant treatment in COVID-19: a narrative review.). Pulmonary hypertension (PH) and right ventricular dysfunction (RVD) have been demonstrated to correlate with more severe COVID-19 symptoms and worse in-hospital clinical outcomes (2Shafiabadi Hassani N Shojaee A Khodaprast Z Sepahvandi R Shahrestanaki E Rastad H Echocardiographic features of cardiac injury related to COVID-19 and their prognostic value: a systematic review.). RVD and PH can be assessed using transthoracic echocardiography through measurement of right ventricular diameter, right ventricular systolic pressure (RVSP), and tricuspid annular plane systolic excursion (TAPSE) (2Shafiabadi Hassani N Shojaee A Khodaprast Z Sepahvandi R Shahrestanaki E Rastad H Echocardiographic features of cardiac injury related to COVID-19 and their prognostic value: a systematic review.,3Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American society of echocardiography and the European association of cardiovascular imaging.). TAPSE is a measurement of the distance traveled by the tricuspid valve along its longitudinal axis during a cardiac cycle (3Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American society of echocardiography and the European association of cardiovascular imaging.). This measurement is used to describe right ventricular systolic function. TAPSE values under 1.7 cm are associated with RVD (2Shafiabadi Hassani N Shojaee A Khodaprast Z Sepahvandi R Shahrestanaki E Rastad H Echocardiographic features of cardiac injury related to COVID-19 and their prognostic value: a systematic review.,3Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American society of echocardiography and the European association of cardiovascular imaging.).Inhaled pulmonary vasodilator medications have been described as therapy for refractory hypoxia due to PH. One trial of inhaled epoprostenol for COVID-19 induced ARDS with refractory hypoxia showed benefit in the most severe cases (4Responsiveness of inhaled epoprostenol in respiratory failure due to COVID-19.). Similar agents have been studied for acute PH with RVD caused by pulmonary embolism (PE) with some benefit in the ED setting (5Kline JA Hall CL Jones AE Puskarich MA Mastouri RA Lahm T. Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial.). Inhaled nitric oxide (iNO) is being explored as a potential treatment for ARDS caused by COVID-19 and has been shown in small studies to improve arterial oxygenation (6Lotz C Muellenbach RM Meybohm P Mutlak H Lepper PM Rolfes C-B et al.Effects of inhaled nitric oxide in COVID-19–induced ARDS – is it worthwhile?.,7Feng W-X Yang Y Wen J Liu Y-X Liu L Feng C. Implication of inhaled nitric oxide for the treatment of critically ill COVID-19 patients with pulmonary hypertension.).The logistics of administering inhaled or intravenous pulmonary vasodilators is cumbersome and often not possible outside of an intensive care unit. Nitroglycerin is widely available in most EDs. Inhaled nitroglycerin (iNTG) has been studied for treatment of pulmonary hypertension as it acts rapidly as a pulmonary vasodilator via nitric oxide donation mechanisms when applied to the pulmonary vasculature (8Schütte H Grimminger F Otterbein J Spriestersbach R Mayer K Walmrath D et al.Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.). In the perioperative setting iNTG has been shown to be a potent pulmonary vasodilator without causing systemic vasodilation (9Mandal B Kapoor PM Chowdhury U Kiran U Choudhury M. Acute hemodynamic effects of inhaled nitroglycerine, intravenous nitroglycerine, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension.). It has been discussed as a treatment for massive PE outside of the setting of COVID-19, but has not been systematically studied.Case Report

During the COVID-19 pandemic, a 56 year-old-male with no known past medical history presented to the emergency department by ambulance. He described one week of generalized malaise, and one day of worsening dyspnea. He denied a history of smoking or prior venous thromboembolic events. He denied experiencing lower extremity swelling, syncope, or palpitations. He reported a positive COVID-19 test the day prior.

Upon presentation, the patient was in severe respiratory distress with increased work of breathing and accessory muscle use. Lung sounds were diminished bilaterally. Physical examination was otherwise without tracheal deviation, jugular venous distension, or lower extremity edema. Initial vital signs were notable for a heart rate of 131 beats per minute and a blood pressure of 116/67 mmHg. Oxygen saturation was 62% on room air and 94% on a nonrebreather mask at 15 liters per minute with a respiratory rate of 48. Bilevel positive airway pressure (BiPAP) was initiated and set to provide 5 mmHg of expiratory positive airway pressure, an additional 7 mmHg of inspiratory positive airway pressure and 100% FiO2 which improved the patient's work of breathing. The patient's pulse oximetry improved to 95% after intervention. He remained tachycardic at a rate of 129 beats per minute with a blood pressure of 100 / 60 mmHg. Higher inspiratory pressures were considered, but it was felt an inspiratory pressure of 12mmHg adequately improved the patient's work of breathing and that higher pressures did not warrant the risk of further hypotension.

An upright chest radiograph revealed bilateral multifocal patchy airspace disease consistent with his known COVID-19 infection (Figure 1). An ECG was performed immediately after stabilization showing sinus tachycardia and an incomplete right bundle branch block without any acute ischemic changes. Initial laboratory results revealed renal dysfunction with creatinine of 1.5 mg/dL presumed to be acute, leukocytosis to 20,300, a troponin elevation at 0.29 ng/mL (normal range: 10Festic E Bansal V Kor DJ Gajic O. SpO2/FiO2 Ratio on hospital admission is an indicator of early acute respiratory distress syndrome development among patients at risk.).

Figure 1AP single view chest x-ray with diffuse patchy opacities

The patient demonstrated worsening hypotension within his first hour of arrival, with a systolic blood pressure of 80mmHg. Pulmonary CT angiography as interpreted by the radiologist revealed bilateral segmental pulmonary emboli and extensive bilateral ground glass opacities consistent with COVID-19 pneumonia. Point of care echocardiography performed by the emergency physician demonstrated right ventricular dilation with systolic septal bowing of the interventricular septum into the left ventricle, tricuspid annular plane systolic excursion (TAPSE) of 1.08 cm (Figure 2 A-C), and right ventricular systolic pressure of 39.66 mmHg.  These markers of RVD are associated with increased morbidity and mortality in the setting of pulmonary embolism and have been shown to correlate with increased morbidity and mortality in COVID-19 (2Shafiabadi Hassani N Shojaee A Khodaprast Z Sepahvandi R Shahrestanaki E Rastad H Echocardiographic features of cardiac injury related to COVID-19 and their prognostic value: a systematic review.).

Figure 2Point of Care Echocardiogram A) Parasternal short axis still image showing deviation of the interventricular septum into the left ventricle indicative of right ventricular pressure overload. B) Apical four chamber still image showing dilated right ventricle with M mode spike placed over the tricuspid plane edge for measurement of Tricuspid Annular Plane Systolic Excursion (TAPSE). C) M-mode tracing of the tricuspid plane edge for measurement of Tricuspid Annular Plane Systolic Excursion (TAPSE) of 1.08 cm indicating right heart dysfunction

Given the patient's progressive hypotension, further treatment modalities were explored. No crystalloid volume resuscitation was administered. Catheter directed fibrinolytic therapy was considered with a multidisciplinary PE team, but the patient was ultimately felt to be too unstable. Vasopressor support was held at bedside ready to deploy but was ultimately never given as the patient's mean arterial pressure did not persist under 65 mmHg despite this significant drop in blood pressure

The patient was given iNTG 2.4mg (200 mcg/mL) via inline closed-circuit nebulizer over the next 60 minutes. Minutes after initiating iNTG, RVD was reevaluated and TAPSE improved.  Serial measurements are shown in Figure 3. Systemic thrombolytic infusion was started at the third data point, 12 minutes after iNTG. Alteplase 100 mg was given over two hours without a bolus dose. The first dose of iNTG was completed after 60 minutes. The next evaluation of right ventricular function 13 minutes after the iNTG treatment was completed showed recurrent RVD. Treatment with iNTG was resumed and 10 minutes after resumption, RVD was again improved - see the final data point in Figure 3.

Figure 3Plot of right heart function assessed by Tricuspid Annular Systolic Excursion over time. Nebulized nitroglycerin (iNTG) was started just after the first plotted time point, iNTG dose completed at approximately 63 minutes, and restarted immediately after the 73 minutes assessment. Systemic thrombolytic therapy was started at 12 minutes and continued for two hours uninterrupted.

During this two-hour time period of initial treatment, non-invasive positive pressure ventilation settings were maintained at the initial pressure settings and a constant 100% FiO2. The patient's blood pressure continued to trend upwards - from a systolic blood pressure nadir of 74 mmHg to a maximum of 86 mmHg - and his work of breathing continued to improve, with a respiratory rate of 30 breaths per minute at the time of final reassessment.

The patient was admitted to the medical ICU with steadily improving hemodynamics. Nebulized nitroglycerin therapy was not continued inpatient, though he was treated with standard therapies including dexamethasone, remdesivir, broad spectrum antibiotics and therapeutic anticoagulation. The intensivist's point of care echocardiogram upon ICU admission was similar to the emergency physician's with a dilated right ventricle. By day 3 of hospitalization, right ventricular dysfunction was no longer present on a cardiology performed echocardiogram, which showed a TAPSE of 2.6 cm and RVSP of 26 mmHg.

The patient's ICU course was protracted and complicated. His respiratory support requirement gradually worsened from intermittent BiPAP to full time BiPAP over the course of the next week to eventually requiring intubation on hospital day 9. On hospital day 11, a cardiology performed echocardiogram showed recurrent RVD. Inhaled epoprostenol was administered for refractory hypoxia despite aggressive respiratory support in the setting of recurrent PH. Despite these measures the patient ultimately died on hospital day 25, intubated in the intensive care unit.

Discussion

Here we describe our experience using nebulized nitroglycerin with systemic thrombolytic therapy to treat a hemodynamically unstable patient's acute right ventricular dysfunction which was caused by COVID-19 induced ARDS complicated by pulmonary emboli.

Systemic thrombolytic therapy was initiated for this patient's profound pulmonary hypertension. The patient's PH and vital sign abnormalities were due in part to COVID-19 induced ARDS and in part due to acute PE. At the time, the treating physicians felt that the patient's hemodynamic instability and echo findings were primarily related to ARDS rather than segmental PEs. However, we also recognized COVID-19 induced ARDS may be associated with overwhelming micro thromboemboli (1Carfora V Spiniello G Ricciolino R Di Mauro M Migliaccio MG Mottola FF et al.Anticoagulant treatment in COVID-19: a narrative review.) and as such the decision was made to administer full dose alteplase 100 mg over two hours without bolus dosing in accordance with FDA guidelines for the management of PE (). Thrombolysis has been retrospectively reviewed in severe COVID-19 pneumonia with concern for PE by Arachchillage et al who found significant improvement in PaO2/FiO2 ratios 24 hours after thrombolytic therapy infusion (11Arachchillage DJ Stacey A Akor F Scotz M Laffan M. Thrombolysis restores perfusion in COVID-19 hypoxia.). Dosing for thrombolytic therapies specific to COVID-19 induced acute PH have yet to be determined. Vasopresor support was held at bedside ready to deploy, but was ultimately never used as the patient's mean arterial pressure did not persist under 65 mmHg despite his significant drop in blood pressure.This patient was given nebulized nitroglycerin (iNTG) 2.4mg (200 mcg/mL) via inline closed-circuit nebulizer over 60 minutes. This dose provided approximately 5.8 micrograms per kilogram per minute of nebulized nitroglycerin (9Mandal B Kapoor PM Chowdhury U Kiran U Choudhury M. Acute hemodynamic effects of inhaled nitroglycerine, intravenous nitroglycerine, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension.). Inhaled nitroglycerin has been described as a treatment for PH in the perioperative setting (9Mandal B Kapoor PM Chowdhury U Kiran U Choudhury M. Acute hemodynamic effects of inhaled nitroglycerine, intravenous nitroglycerine, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension.), but has not been rigorously studied in the ED setting. The rapid onset of action of this medication via nebulization at 3 - 5 minutes is well suited to acutely ill patients in the ED setting, and the duration of effect was found to persist for up to 30 minutes (9Mandal B Kapoor PM Chowdhury U Kiran U Choudhury M. Acute hemodynamic effects of inhaled nitroglycerine, intravenous nitroglycerine, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension.). Studies of other inhaled pulmonary vasodilators for acute RVD, such as inhaled nitric oxide (iNO), are ongoing (5Kline JA Hall CL Jones AE Puskarich MA Mastouri RA Lahm T. Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial.), but the logistics of providing iNO in the ED setting may be onerous.The addition of iNTG to this patient's treatment appears to have improved right ventricular dysfunction and work of breathing within minutes of starting therapy - see the second data point in Figure 3. Systemic thrombolytic therapy was started at the third data point and continued for two hours.This case highlights the acute changes to right heart function caused by iNTG and systemic thrombolytic therapy. This is especially evident in the last three data points of Figure 3.  The initial iNTG treatment was completed at 60 minutes, followed by decompensated right ventricular function upon reevaluation at 73 minutes. Right ventricular function improved once iNTG was re-initiated. The pharmacokinetic properties of alteplase without bolus dose suggest peak effect to be reached approximately 6 hours after completion of the 2 hour infusion (13Goldhaber Samuel Z. Agnelli Giancarlo Levine Mark N. Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis: an international multicenter randomized trial.). Therefore the majority of the improvement seen in this patient's RVD may be attributed to iNTG rather than thrombolytic therapy.

This case calls for prospective study of inhaled pulmonary vasodilators medications such as nitroglycerin in the emergency department setting for treatment of severe COVID-19 induced ARDS as well as PH caused by PE without COVID-19.

 Why Should an Emergency Physician Be Aware of This?

In this case of severe COVID-19 ARDS and PE with right ventricular dysfunction, inhaled nitroglycerin improved this patient's acute pulmonary hypertension. This novel use of a common medication may provide a new treatment option for acute pulmonary hypertension which is otherwise poorly addressed by standard ED therapies. This case report serves as evidence to prospectively study both inhaled nitroglycerin and systemic thrombolysis for the treatment of COVID-19 ARDS and pulmonary embolism with right ventricular dysfunction.