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COVID-19 Resource Center

Disclosures: Berra reports receiving salary support from K23 HL128882/NHLBI National Institutes of Health as principal investigator for his work on hemolysis and nitric oxide. He also receives technologies and devices from iNO Therapeutics LLC, Praxair Inc., and Masimo Corp. for clinical research and receives a grant from iNO Therapeutics LLC.
September 04, 2020
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Nitric oxide may benefit pregnant women with severe COVID-19

Disclosures: Berra reports receiving salary support from K23 HL128882/NHLBI National Institutes of Health as principal investigator for his work on hemolysis and nitric oxide. He also receives technologies and devices from iNO Therapeutics LLC, Praxair Inc., and Masimo Corp. for clinical research and receives a grant from iNO Therapeutics LLC.
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In pregnant women with severe or critical COVID-19, inhaled nitric oxide therapy was well-tolerated and associated with improved respiratory rates and oxygenation, according to research published in Obstetrics & Gynecology.

Researchers evaluated six pregnant patients admitted to Massachusetts General Hospital with severe or critical COVID-19 from April to June. Patients received a high-dose concentration of nitric oxide while awake through a snug-fitting mask that was connected to a breathing circuit.

Quote from Berra on nitric oxide in pregnant women with COVID-19

The patients received nitric oxide inhalation as a rescue therapy based on the clinical team’s request within 48 hours of hospitalization. All patients received supplemental oxygen in the first 48 hours, four were treated in the ICU for 3 to 7 days, and two needed to be intubated for 30 hours to 14 days.

When patients were medically ventilated, researchers suspended high-dose concentrations of nitric oxide and instead delivered continuous low-dose inhaled nitric oxide through the ventilator.

Overall, 39 high-dose (160-200 ppm) nitric oxide treatments were administered to the patients.

Researchers found that patients’ systemic oxygenation improved immediately during treatment sessions and there was a reduction of tachypnea during all sessions, indicating an improvement in cardiopulmonary function.

During hospitalization, three patients delivered four neonates, and three patients remained pregnant at discharge.

Five of the women tested negative for severe SARS-CoV-2 twice by day 28, with one patient remaining positive.

Healio Primary Care spoke with study co-author Lorenzo Berra, MD, the Reginald Jenney Associate Professor of Anaesthesia at Massachusetts General Hospital (MGH), to learn more about the findings and nitric oxide treatment in pregnant women with severe COVID-19.

Q: Should more physicians begin treating pregnant women hospitalized with COVID-19 with nitric oxide?

A: Yes — an absence of safe targeted treatments for pregnant women with severe COVID-19 prompted us to study inhaled nitric oxide (iNO) to destroy the virus and prevent progression of the disease. In our case series of six pregnant patients with COVID-19, our treatment consisted of antimicrobial, high-dose (160-200 parts per million, ppm) inhaled NO by mask for 30 to 60 minutes twice a day. The patients tolerated the treatment well, and we observed a reduction in their respiratory rate and improved oxygenation during NO breathing. Five of six patients did not receive other antiviral agents (e.g., remdesivir) and had a PCR negative nasal swab for SARS-CoV-2 within 22 days after commencing NO treatment.

Q: Is this treatment widely available to physicians caring for patients with severe COVID-19?

A: Inhaled nitric oxide was approved by the FDA in December 1999 for the treatment of persistent pulmonary hypertension in hypoxic newborns. Since then, NO has saved the lives of hundreds of thousands of babies. Inhaled NO gas has been used for off-label applications in many pediatric and adult clinical conditions (e.g., pulmonary hypertension in pregnancy, cardiac surgery and acute respiratory distress syndrome). While NO is widely used in mechanically ventilated patients, NO is less frequently used in patients who are spontaneously breathing. Our team at MGH developed a new delivery system that allows stable and safe delivery of high concentrations of iNO in spontaneously breathing patients. The use of high dose iNO requires specialized personnel to manage the delivery system and continuously monitor the patient.

Q: Why would treating pregnant women with nitric oxide be better than mechanical ventilation?

A: The CDC reported that pregnant patients with severe forms of COVID-19 are at high risk for hospitalization, ICU admission and mechanical ventilation. A study during the first phase of the pandemic in New York showed that pregnant patients with COVID-19 who are intubated and mechanically ventilated have poor outcomes. Thus, preventing the deterioration due to this respiratory disease in its early stages, and avoiding mechanical ventilation is of utmost importance. Mechanical ventilation also requires giving IV anesthetic drugs which can enter the maternal and fetal circulation.

Q: Previously, a study found that pregnant women with COVID-19 had placental damage consistent with maternal vascular malperfusion. Could treatment with nitric oxide help prevent this damage?

A: Nitric oxide acts on the pulmonary smooth muscle and is rapidly metabolized by circulating blood in the lungs. Thus, we do not expect a direct impact of iNO on placental or fetal perfusion. However, there are beneficial indirect systemic effects of iNO. Due to its rapid onset of action, iNO promptly improves systemic oxygenation by vasodilatation of the ventilated regions of injured lungs, resulting in decreased right-to-left shunting and improved ventilation-perfusion matching. The present report showed a rapid increase in oxygenation upon iNO initiation. This is of particular clinical interest in pregnancy due to increased oxygen demand and the potential to rapidly improve placental oxygenation and oxygen delivery to the fetus. Maternal hypoxia is associated with an increased risk of miscarriage and fetal demise. Improved oxygenation by iNO therapy suggest that longer periods of NO inhalation, possibly at lower concentrations, might be useful between high dose treatments in the most hypoxic of patients.

Our decision to use 160-200 ppm inhaled NO in severe/critical COVID-19 pregnant patients was based on prior reports showing the antibacterial and antiviral effects of NO. Specifically, laboratory experiments performed by Keyaerts et al. at the University of Leuven (Belgium) showed that NO released from NO-donor molecules exert a direct antiviral effect against SARS-CoV-1 in vitro. The two viruses responsible for the epidemics of 2002-03 (SARS-CoV-1) and 2019-20 (SARS-CoV-2) show wide genetic similarities. We hypothesize that free radical NO gas exerts virucidal action by direct nitrosation of critical virion proteins required for infection, replication, transmission and, eventually, placenta invasion. In this report, five out of six patients tested negative by RT-PCR by 28 days from admission, which facilitated lactation and close bonding with their newborns. Three of the six women thus far have delivered four healthy babies, including a set of twins, while in the hospital. Certainly, we need future studies to further investigate the indirect effects of iNO therapy on placental and fetal perfusion.

Q: What additional research is needed to investigate nitric oxide treatment in pregnant women?

A: We created a network of five hospitals: Massachusetts General Hospital (Boston, Massachusetts), Louisiana State University (Shreveport, Louisiana), Beth Israel Deaconess Medical Center (Boston, Massachusetts), and the University of Alabama at Birmingham (Birmingham, Alabama). We are currently performing four randomized clinical trials on the use of iNO in COVID-19 patients. These trials will evaluate the effectiveness of iNO against COVID-19 in different settings and levels of disease severity. One trial will determine if iNO prevents disease in health care workers at high risk of exposure for COVID-19. A second trial studies whether iNO therapy prevents readmission of patients discharged from the emergency department. The third trial examines whether iNO reduces the need for intubation and mechanical ventilation in spontaneously breathing hospitalized patients with mild forms (or symptoms) of COVID-19. A fourth trial explores whether iNO therapy improves oxygenation in intubated patients with severe COVID-19. Finally, we are now considering a large randomized multicenter clinical trial on iNO therapy in pregnant patients with severe COVID-19.

References:

Keyaerts E, et al. Int J Infect Dis. 2004;doi:10.1016/j.ijid.2004.04.012.

Safaee Fakhr, B. Obstet Gynecol. 2020;doi:10.1097/AOG.0000000000004128.

Gianni S, et al. Nitric Oxide. 2020;doi: 10.1016/j.niox.2020.08.004.