Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147–150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

Hypothesis article: Nitric oxide depletion may aggravate COVID-19 symptoms. A new therapy could help

The Corona virus SARS-CoV2 that causes COVID-19 has effects that until now have not been explained. The widespread damage of SARS-CoV2, the comorbidities in critically ill COVID-19 patients, and the symptoms of post-COVID-19 patients show striking similarities with conditions that are related to depletion of nitric oxide (NO) in the human body. Many of the symptoms of the disease may be caused by acute depletion of NO by the immune system. Patients with the highest COVID-19 burden often have comorbidities that are related to chronic depletion of NO. Post-COVID-19 health problems may be caused by earlier depletion of NO. Successful therapy requires sufficient NO levels. Supplementation with NO will increase immunity, help prevent thrombosis, and improve breathing, kidney functions, blood flow and oxygenation in patients, elderly patients and patients with comorbidities in particular. Furthermore, NO helps to prevent SARS-CoV2 from entering the human cell and to suppress viral RNA production. NO is not easy to supplement. A few SARS patients have been treated with inhaled NO with positive results, but inhaled NO can only deliver small quantities of NO. A new therapy has been developed to more effectively supplement NO. It combines the ingestion of nitrates (as NO donor), N-acetylcysteine and vitamin C (promoting NO metabolism) with electrostimulation of the muscles (to trigger the release of NO). It is expected that this therapy can ease the most serious symptoms of (post) COVID-19, especially for elderly and people with comorbidities. A patent has been applied for.

Abstract 17272: Frequency of Acute Vasodilator Response in Incident and Prevalent Patients With Pulmonary Arterial Hypertension (Group 1): Results From the Pulmonary Vascular Disease Omics (PVDOMICS) Study

Introduction: The prevalence of acute vasodilator response (AVR) to inhaled NO (defined as a reduction in mPAP ≥ 10 mmHg with an absolute value of mPAP ≤ 40 mmHg with increased/unchanged CO) is reported to be around 12% in incident patients with idiopathic PAH (IPAH). The prevalence of AVR, however, is reportedly lower in other disease-associated PAH in Group 1, such as connective tissue disease (CTD). Furthermore, the prevalence of AVR for combined inhaled NO and oxygen, and in patients on PAH therapy (prevalent cohort), is less known. Hypothesis: We hypothesized there would be differences in the prevalence of AVR in PAH subgroups in the large PVDOMICS cohort of incident and prevalent patients. Methods: Group 1 PAH patients enrolled in PVDOMICS underwent right heart catheterization for baseline measurements. AVR was then measured in response to 100% inhaled oxygen (O 2 ) and 100% O 2 plus NO at 40 ppm (O 2 +NO) for 5 min each before hemodynamic measurements. Details of the PVDOMICS methodology and core adjudication of hemodynamic measurements were reported previously. Rates of AVR to 100% O 2 and 100% O 2 +NO were compared between incident and prevalent patients in each PAH subgroup. Results: 351 patients, mostly female (73%), average age of 52.9 years, with mostly prevalent disease (87%) and an average of 4 years from PAH diagnosis, underwent AVR assessment. A positive AVR was found in 0.6% of patients in response to 100% oxygen and 6% of patients in response to 100%+NO for the overall cohort. AVR was similar in incident and prevalent IPAH patients (6 and 6.9%, respectively). It was, however, 0% and 6.9%, in incident vs. prevalent CTD-PAH patients, respectively. There were no responders to either challenge in any other PAH subgroup. Conclusions: The prevalence of AVR is relatively rare in IPAH and CTD-PAH (~ 6%) and absent in other subgroups. There was no response to 100% O2 alone, suggesting specificity of AVR to NO in PAH. AVR is more common than previously reported in CTD-PAH, but only in prevalent disease. Whether the latter is related to long-term PAH therapy affecting pulmonary vasomotor response and/or vascular remodeling in these patients would warrant further studies.

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease

Introduction. Mycobacterium abscessus is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary M. abscessus disease, and examined heterogeneity of response to NO in vitro. Methods. In the compassionate-use treatment, a 24-year-old CF patient with pulmonary M. abscessus was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. In vitro susceptibility tests were performed against patient’s isolate and comparison clinical isolates and quantified by Hill’s slopes calculated from time–kill curves. Results. M. abscessus lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. In vitro susceptibility tests showed a dose-dependent NO effect on M. abscessus susceptibility and significant heterogeneity in response between M. abscessus clinical isolates. The patient’s isolate was found to be the least susceptible strain in vitro. Conclusion. These results demonstrate heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19

Introductionthe current worldwide outbreak of Coronavirus disease 2019 (COVID-19) due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities. Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value. To date there is still no available treatment for SARS-CoV-2. Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirus-mediated acute respiratory syndrome, and this can be related to its viricidal effect. The time from the symptoms’ onset to the development of severe respiratory distress is relatively long. We hypothesize that high concentrations of inhaled NO administered during early phases of COVID-19 infection can prevent the progression of the disease.Methods and analysisThis is a multicenter randomized controlled trial. Spontaneous breathing patients admitted to the hospital for symptomatic COVID-19 infection will be eligible to enter the study. Patients in the treatment group will receive inhaled NO at high doses (140-180 parts per million) for 30 minutes, 2 sessions every day for 14 days in addition to the hospital care. Patient in the control group will receive only hospital care. The primary outcome is the percentage of patients requiring endotracheal intubation due to the progression of the disease in the first 28 days from enrollment in the study. Secondary outcomes include mortality at 28 days, proportion of negative test for SARS-CoV-2 at 7 days and time to clinical recovery.Ethics and disseminationThe trial protocol has been approved at the Investigation Review Boards of Xijing Hospital (Xi’an, China) and The Partners Human Research Committee of Massachusetts General Hospital (Boston, USA) is pending. Recruitment is expected to start in March 2020. Results of this study will be published in scientific journals, presented at scientific meetings, and on related website or media in fighting this widespread contagious disease.Trial registrationClinicaltrials.gov. NCT submitted

Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism

Background: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism. Methods: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat ( n=6), sildenafil ( n=6), inhaled NO ( n=6) or vehicle ( n=6). Sham animals ( n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis. Results: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs. baseline: 107±6 dynes, p<0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: –158±35, sildenafil: –224±35, inhaled NO: –156±35 dynes, p<0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678±41 vs. vehicle 1081±93 dynes, p=0.02) and increased cardiac output (sildenafil 8.8±0.8 vs. vehicle: 5.9±0.2 L/min, p<0.001). Systemic blood pressure was unaltered in all treatment groups. Conclusion: Stimulation of the NO–sGC–cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.