iNO Therapy Research Articles

Impact of inhaled nitric oxide therapy in patients with cardiogenic shock treated with veno-arterial extracorporeal membrane oxygenation combined with Impella

Abstract Background Mortality rates remain high in patients with cardiogenic shock (CS) requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO) combined with Impella (ECPELLA) support. Early weaning from VA-ECMO may be the first step in reducing mortality in these patients. Inhaled nitric oxide (iNO) therapy improves right ventricular function by decreasing pulmonary arterial resistance, resulting in increased Impella flow rate, which may facilitate early withdrawal of VA-ECMO and improve survival. Purpose The purpose of this study was to investigate the prognostic impact of iNO therapy on ECPELLA patients. Methods We retrospectively studied consecutive patients with CS due to acute myocardial infarction (AMI-CS) or decompensated heart failure (ADHF-CS) supported with ECPELLA from September 2019 to January 2024 at our hospital. The VA-ECMO withdrawal rate, time to withdrawal, and 30-day survival were compared for ECPELLA patients with and without iNO therapy. Results A total of 47 patients were included (AMI-CS, n=26, and ADHF-CS, n=21). Of these, 21 patients (44.7%) were treated with iNO therapy. Patient characteristics were not significantly different between those with and without iNO therapy, including age, gender, percentage of cardiopulmonary arrest or acute coronary syndrome, and lactate levels at mechanical circulatory support induction. Patients receiving iNO therapy had significantly higher VA-ECMO withdrawal rates (90% vs. 50%, P=0.003) and shorter time to VA-ECMO withdrawal (5.0±1.3 vs. 7.8±5.6 days, P=0.04) than those not receiving iNO therapy. Furthermore, Kaplan-Meier analysis demonstrated that the 30-day survival rate was significantly higher in patients receiving iNO therapy than those without (P=0.003, Figure). Conclusion Adjuvant iNO therapy for CS patients supported by ECPELLA facilitates early withdrawal of VA-ECMO and improve survival representing a useful therapeutic option.Figure

Impact of low dose inhaled nitric oxide treatment in spontaneously breathing and intubated COVID-19 patients: a retrospective propensity-matched study

BackgroundThe benefit of Inhaled nitric oxide (iNO) therapy in the setting of COVID-19-related ARDS is obscure. We performed a multicenter retrospective study to evaluate the impact of iNO on patients with COVID-19 who require respiratory support.MethodsThis retrospective multicenter study included COVID-19 patients enrolled in the SCCM VIRUS COVID-19 registry who were admitted to different Mayo Clinic sites between March 2020 and June 2022 and required high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), or invasive mechanical ventilation (IMV). Patients were included in the ‘spontaneously breathing’ group if they remained non-intubated or were initiated on an HFNC (± NIV) before intubation. Patients who got intubated without prior use of an HFNC (± NIV) were included in the ‘intubated group.’ They were further divided into categories based on their iNO usage. Propensity score matching (PSM) and inverse propensity of treatment weighting (IPTW) were performed to examine outcomes.ResultsAmong 2767 patients included in our analysis, 1879 belonged to spontaneously breathing (153 received iNO), and 888 belonged to the intubated group (193 received iNO). There was a consistent improvement in FiO2 requirement, P/F ratio, and respiratory rate within 48 h of iNO use among both spontaneously breathing and intubated groups. However, there was no significant difference in intubation risk with iNO use among spontaneously breathing patients (PSM OR 1.08, CI 0.71–1.65; IPTW OR 1.10, CI 0.90–1.33). In a time-to-event analysis using Cox proportional hazard model, spontaneously breathing patients initiated on iNO had a lower hazard ratio of in-hospital mortality (PSM HR 0.49, CI 0.32–0.75, IPTW HR 0.40, 95% CI 0.26–0.62) but intubated patients did not (PSM HR: 0.90; CI 0.66–1.24, IPTW HR 0.98, 95% CI 0.73–1.31). iNO use was associated with longer in-hospital stays, ICU stays, ventilation duration, and a higher incidence of creatinine rise.ConclusionsThis retrospective propensity-score matched study showed that spontaneously breathing COVID-19 patients on HFNC/ NIV support had a decreased in-hospital mortality risk with iNO use in a time-to-event analysis. Both intubated and spontaneously breathing patients had improvement in oxygenation parameters with iNO therapy but were associated with longer in-hospital stays, ICU stays, ventilation duration, and higher incidence of creatinine rise.

Machine Learning Analysis of Predictors for Inhaled Nitric Oxide Therapy Administration Time Post Congenital Heart Disease Surgery: A Single-Center Observational Study.

Background Congenital heart disease (CHD) is a structural deformity of the heart present at birth. Pulmonary hypertension (PH) may arise from increased blood flow to the lungs, persistent pulmonary arterial pressure elevation, or the use of cardiopulmonary bypass (CPB) during surgical repair. Inhaled nitric oxide (iNO) selectively reduces high blood pressure in the pulmonary vessels without lowering systemic blood pressure, making it useful for treating children with postoperative PH due to heart disease. However, reducing or stopping iNO can exacerbate postoperative PH and hypoxemia, necessitating long-term administration and careful tapering. This study aimed to evaluate, using machine learning (ML), factors that predict the need for long-term iNO administration after open heart surgery in CHD patients in the postoperative ICU, primarily for PH management. Methods We used an ML approach to establish an algorithm to predict 'patients with long-term use of iNO' and validate its accuracy in 34 pediatric postoperative open heart surgery patients who survived and were discharged from the ICU at Kagoshima University Hospital between April 2016 and March 2019. All patients were started on iNO therapy upon ICU admission. Overall, 16 features reflecting patient and surgical characteristics were utilized to predict the patients who needed iNO for over 168 hours using ML analysis with AutoGluon. The dataset was randomly classified into training and test cohorts, comprising 80% and 20% of the data, respectively. In the training cohort, the ML model was constructed using the important features selected by the decrease in Gini impurity and a synthetic oversampling technique. In the testing cohort, the prediction performance of the ML model was evaluated by calculating the area under the receiver operating characteristics curve (AUC) and accuracy. Results Among 28 patients in the training cohort, five needed iNO for over 168 hours; among six patients in the testing cohort, one needed iNO for over 168 hours. CPB, aortic clamp time, in-out balance, and lactate were the four most important features for predicting the need for iNO for over 168 hours. In the training cohorts, the ML model achieved perfect classification with an AUC of 1.00. In the testing cohort, the ML model also achieved perfect classification with an AUC of 1.00 and an accuracy of 1.00. Conclusion The ML approach identified that four factors (CPB, in-out balance, aortic cross-clamp time, and lactate) are strongly associated with the need for long-term iNO administration after open heart surgery in CHD patients. By understanding the outcomes of this study, we can more effectively manage iNO administration in postoperative open heart surgery in CHD patients with PH, potentially preventing the recurrence of postoperative PH and hypoxemia, thereby contributing to safer patient management.

Magnetic Resonance Imaging Assessment of Pulmonary Vascularity in Preterm Infants with Bronchopulmonary Dysplasia

Introduction: Pulmonary hypertension often complicates bronchopulmonary dysplasia (BPD) and infants with BPD plus pulmonary hypertension experience higher mortality rates. Current methods to evaluate pulmonary hypertension fail to evaluate the primary cause of this disease. We hypothesize that preterm infants with BPD experience altered pulmonary vascular growth and that magnetic resonance imaging (MRI) can be used to assess vascularity in BPD. Methods: In this observational cohort study, preterm infants with BPD (n = 33) and controls (n = 6) received a postnatal chest MRI that included a 2-dimensional time-of-flight acquisition. Semi-automatic segmentation was performed to measure vascularity parameters including vascular volume and density (vascular density = vascular volume/lung volume). Results: Vascular volume on MRI increases with post-menstrual age (877.2 mm3/week); however, the vascular density does not significantly change. Vascular volume is higher in infants with more severe BPD (p < 0.002), but vascular density did not significantly change when comparing mild, moderate, and severe BPD. Vascular density in infants with severe BPD requiring tracheostomy trended lower when compared to infants not requiring tracheostomy (0.18 mm3/mm3 vs. 0.27 mm3/mm3, p = 0.06). Vascular density increases with increasing days of inhaled nitric oxide (iNO) therapy in infants with severe BPD (0.02 mm3/mm3/week of iNO, rho = +0.56, p = 0.03). Conclusion: Neonatal MRI can be used to assess pulmonary vascularity in preterm infants with BPD. Infants with BPD experience altered vascular growth and while higher vascular volume is associated with more severe BPD, lower vascular density trends toward worse clinical outcomes. Vascular density increases with iNO therapy in severe BPD.

A Comparative Investigation of the Pulmonary Vasodilating Effects of Inhaled NO Gas Therapy and Inhalation of a New Drug Formulation Containing a NO Donor Metabolite (SIN-1A).

Numerous research projects focused on the management of acute pulmonary hypertension as Coronavirus Disease 2019 (COVID-19) might lead to hypoxia-induced pulmonary vasoconstriction related to acute respiratory distress syndrome. For that reason, inhalative therapeutic options have been the subject of several clinical trials. In this experimental study, we aimed to examine the hemodynamic impact of the inhalation of the SIN-1A formulation (N-nitroso-N-morpholino-amino-acetonitrile, the unstable active metabolite of molsidomine, stabilized by a cyclodextrin derivative) in a porcine model of acute pulmonary hypertension. Landrace pigs were divided into the following experimental groups: iNO (inhaled nitric oxide, n = 3), SIN-1A-5 (5 mg, n = 3), and SIN-1A-10 (10 mg, n = 3). Parallel insertion of a PiCCO system and a pulmonary artery catheter (Swan-Ganz) was performed for continuous hemodynamic monitoring. The impact of iNO (15 min) and SIN-1A inhalation (30 min) was investigated under physiologic conditions and U46619-induced acute pulmonary hypertension. Mean pulmonary arterial pressure (PAP) was reduced transiently by both substances. SIN-1A-10 had a comparable impact compared to iNO after U46619-induced pulmonary hypertension. PAP and PVR decreased significantly (changes in PAP: -30.1% iNO, -22.1% SIN-1A-5, -31.2% SIN-1A-10). While iNO therapy did not alter the mean arterial pressure (MAP) and systemic vascular resistance (SVR), SIN-1A administration resulted in decreased MAP and SVR values. Consequently, the PVR/SVR ratio was markedly reduced in the iNO group, while SIN-1A did not alter this parameter. The pulmonary vasodilatory impact of inhaled SIN-1A was shown to be dose-dependent. A larger dose of SIN-1A (10 mg) resulted in decreased PAP and PVR in a similar manner to the gold standard iNO therapy. Inhalation of the nebulized solution of the new SIN-1A formulation (stabilized by a cyclodextrin derivative) might be a valuable, effective option where iNO therapy is not available due to dosing difficulties or availability.

Expert consensus on clinical application of inhaled nitric oxide therapy (2024 edition)

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that has been used in newborns, children, and adults with various cardiopulmonary diseases to reduce pulmonary artery pressure and improve oxygenation. Currently, there are numerous brands of iNO devices on the market with significant differences in performance, as well as variations in connection and setup. Additionally, adverse reactions such as methemoglobinemia may occur during iNO treatment. Therefore, the safety and efficacy of this treatment need to be ensured in clinical practice. To address these concerns and standardize the clinical application of iNO therapy, the Respiratory Care Group of Chinese Thoracic Society and Respiratory Therapist Working Group of Respiratory Career Development Committee, Chinese Association of Chest Physician have organized relevant experts to develop an expert consensus on the clinical application of iNO therapy based on the latest research progress and clinical operational experience. This consensus includes 11 expert consensus recommendations on indications and contraindications of iNO, selection and connection of iNO devices, dose selection and therapeutic effect evaluation of iNO, adverse effects and occupational protection during iNO treatment, transport of patients with iNO, weaning of iNO, cleaning, disinfection and maintenance of iNO devices, and iNO clinical use process and records. The aim is to improve the cognitive and practical ability of clinical practitioners for the standardized application of iNO therapy, so as to ensure the safety and effectiveness of clinical application of iNO therapy.

Efficacy and safety of high doses of inhaled nitric oxide in patients with community-acquired pneumonia: a pilot study

For the first time, the effectiveness and safety of high doses of inhaled nitric oxide (iNO) in patients with community-acquired pneumonia (CAP) has been demonstrated.The aim of the study was to examine the effectiveness and safety of adding iNO to standard treatment for patients with CAP.Methods. A pilot, single-center, prospective, randomized, open-label clinical trial was conducted, which included patients (n = 120) hospitalized with CAP. Randomization was carried out using the blind envelope method. Patients in the main group (n = 60) received iNO through nasal cannulas using the Tianox iNO therapy device (AIT-NO-Ol according to TU 32.50. 21-001-07623615-2017) in addition to the therapy according to the standard of care at the study center. Inhalations were carried out with high doses of NO, namely 200 ppm for 15 minutes 3 times a day, regardless of food intake. Patients in the control group (n = 60) received only the therapy recommended by the standard of care at the study center. Clinical and laboratory parameters were assessed and safety of the therapy was monitored during the study.Results. No significant differences were identified between the main group and the control group in demographic, clinical, laboratory and instrumental data at baseline. Patients receiving iNO as an adjunct to standard therapy had a more significant improvement in clinical symptoms starting from the 3rd day and better oxygenation parameters on the 7th day of therapy. There was a more significant decrease in the level of C-reactive protein on the 5th and 7th days of therapy and a more significant decrease in the level of leukocytes on the 5th day in the main group. The duration of hospitalization in the main group was significantly shorter than that in the control group. NO inhalation was not associated with any side effects and was well tolerated.Conclusion. The use of high doses of NO has a positive effect on the clinical status, markers of inflammation, reduces the length of hospitalization, and demonstrates good tolerability and safety in patients with CAP.

Inhaled nitric oxide and postoperative outcomes in cardiac surgery with cardiopulmonary bypass: A systematic review and meta-analysis

Cardiac surgeries under cardiopulmonary bypass (CPB) are complex procedures with high incidence of complications, morbidity and mortality. The inhaled nitric oxide (iNO) has been frequently used as an important composite of perioperative management during cardiac surgery under CPB. We conducted a meta-analysis of published randomized clinical trials (RCTs) to assess the effects of iNO on reducing postoperative complications, including the duration of postoperative mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay, mortality, hemodynamic improvement (the composite right ventricular failure, low cardiac output syndrome, pulmonary arterial pressure, and vasoactive inotropic score) and myocardial injury biomarker (postoperative troponin I levels). Subgroup analyses were performed to assess the effect of modification and interaction. These included iNO dosage, the timing and duration of iNO therapy, different populations (children and adults), and comparators (other vasodilators and placebo or standard care). A comprehensive search for iNO and cardiac surgery was performed on online databases. Twenty-seven studies were included after removing the duplicates and irrelevant articles. The results suggested that iNO could reduce the duration of mechanical ventilation, but had no significance in the ICU stay, hospital stay, and mortality. This may be attributed to the small sample size of the most included studies and heterogeneity in timing, dosage and duration of iNO administration. Well-designed, large-scale, multicenter clinical trials are needed to further explore the effect of iNO in improving postoperative prognosis in cardiovascular surgical patients.

Occurrence of hyperoxia during iNO treatment for persistent pulmonary hypertension of the newborn: a cohort study

High concentrations of oxygen are often needed to optimize oxygenation in infants with persistent pulmonary hypertension (PPHN), but this can also increase the risk of hyperoxemia. We determined the occurrence of hyperoxemia in infants treated for PPHN. Medical records of infants ≥ 34 + 0 weeks gestational age (GA) who received inhaled nitric oxide (iNO) were retrospectively reviewed for oxygenation parameters during iNO therapy. Oxygen was manually titrated to target arterial oxygen tension (PaO2) 10–13 kPa and peripheral oxygen saturation (SpO2) 92–98%. The main study outcomes were the incidence and duration of hyperoxemia and hypoxemia and the fraction of inspired oxygen (FiO2). A total of 181 infants were included. The median FiO2 was 0.43 (IQR 0.34–0.56) and the maximum FiO2 was 1.0 in 156/181 (86%) infants, resulting in at least one PaO2 > 13 kPa in 149/181 (82%) infants, of which 46/149 (31%) infants had minimal one PaO2 > 30 kPa. SpO2 was > 98% in 179/181 (99%) infants for 17.7% (8.2–35.6%) of the iNO time. PaO2 < 10 kPa occurred in 160/181 (88%) infants, of which 81/160 (51%) infants had minimal one PaO2 < 6.7 kPa. SpO2 was < 92% in 169/181 (93%) infants for 1.6% (0.5–4.3%) of the iNO time. Conclusion: While treatment of PPHN is focused on preventing and reversing hypoxemia, hyperoxemia occurs inadvertently in most patients.What is Known:• High concentrations of oxygen are often needed to prevent hypoxemia-induced deterioration of PPHN, but this can also increase the risk of hyperoxemia.• Infants with persistent pulmonary hypertension may be particularly vulnerable to the toxic effects of oxygen, and hyperoxemia could further induce pulmonary vasoconstriction, potentially worsening the condition.What is New:• Hyperoxemia occurs in the majority of infants with PPHN during treatment with iNO.• Infants with PPHN spent a considerably longer period with saturations above the target range compared to saturations below the target range.

Use of inhaled nitric oxide in COVID-19

Inhaled nitric oxide (iNO) is being considered as a potential therapeutic intervention for COVID-19 and post-COVID syndrome due to its various mechanisms such as vasodilation, antiviral activity, antithrombotic and anti-inflammatory effects. There is currently a lack of information on patient selection criteria, optimal dosing, duration and timing of administration, and methods of administration. These factors are of substantial importance for the efficacy of iNO therapy.Aim. To discuss the physiological basis of using inhaled nitric oxide for treating patients with COVID-19 and post- COVID syndrome, analyze the research findings, and present the achievements in nitric oxide synthesis technology in medicine.Conclusion. The early initiation and use of high-dose iNO appears to be an effective and safe treatment strategy for patients with COVID-19, as it targets the basic pathological mechanisms of the disease. iNO may also be a promising therapeutic option for patients with post-COVID syndrome. However, the optimal dosing regimen, continuous or intermittent, warrants further investigation. Recent advances in nitric oxide synthesis technology are of great significance for the broad practical application of iNO therapy.

A Comprehensive Review of Inhaled Nitric Oxide Therapy: Current Trends, Challenges, and Future Directions.

This comprehensive review explores the multifaceted landscape of inhaled nitric oxide (iNO) therapy, tracing its historical evolution, mechanisms of action, clinical applications, challenges, and future directions. The nitric oxide signaling pathway, characterized by vasodilatory effects and anti-inflammatory properties, forms the foundation of iNO's therapeutic efficacy. Clinical applications are found in neonatal respiratory distress syndrome, pulmonary hypertension, and acute respiratory distress syndrome, showcasing its versatility. However, challenges, including cost considerations, technical intricacies, safety concerns, and resistance, highlight the nuanced landscape surrounding iNO therapy. Implications for clinical practice underscore the need for a tailored and evidence-based approach, considering individual patient characteristics and indications. Recommendations for future research emphasize ongoing exploration, novel indications, and the development of targeted therapies. In conclusion, this review positions iNO as a dynamic and adaptable intervention, poised to reshape therapeutic strategies and enhance patient outcomes in critical care.

Inhaled nitric oxide therapy for preterm infants after 7 days of age: a scoping review protocol

IntroductionInhaled nitric oxide (iNO) use is recommended for persistent pulmonary hypertension of the newborn in term and late preterm infants. Recently, iNO therapy to prevent bronchopulmonary dysplasia (BPD) or rescue...

Mechanistic analysis of the photolytic decomposition of solid-state S-nitroso-N-acetylpenicillamine

S-Nitroso-N-acetylpenicillamine (SNAP) is among the most common nitric oxide (NO)-donor molecules and its solid-state photolytic decomposition has potential for inhaled nitric oxide (iNO) therapy. The photochemical NO release kinetics and mechanism were investigated by exposing solid-state SNAP to a narrow-band LED as a function of nominal wavelength and intensity of incident light. The photolytic efficiency, decomposition products, and the photolytic pathways of the SNAP were examined. The maximum light penetration depth through the solid layer of SNAP was determined by an optical microscope and found to be within 100–200 μm, depending on the wavelength of light. The photolysis of solid-state SNAP to generate NO along with the stable thiyl (RS·) radical was confirmed using Electron Spin Resonance (ESR) spectroscopy. The fate of the RS· radical in the solid phase was studied both in the presence and absence of O2 using NMR, IR, ESR, and UPLC-MS. The changes in the morphology of SNAP due to its photolysis were examined using PXRD and SEM. The stable thiyl radical formed from the photolysis of solid SNAP was found to be reactive with another adjacent thiyl radical to form a disulfide (RSSR) or with oxygen to form various sulfonyl and sulfonyl peroxyl radicals {RS(O)xO·, x = 0 to 7}. However, the thiyl radical did not recombine with NO to reform the SNAP. From the PXRD data, it was found that the SNAP loses its crystallinity by generating the NO after photolysis. The initial release of NO during photolysis was increased with increased intensity of light, whereas the maximum light penetration depth was unaffected by light intensity. The knowledge gained about the photochemical reactions of SNAP may provide important insight in designing portable photoinduced NO-releasing devices for iNO therapy.

Comparative investigation of pulmonary vasodilating effects of inhaled Nitric Oxide (NO) gas therapy and inhalation of SIN-1, a new drug formulation containing an NO-donor metabolite

Abstract Background The management of acute pulmonary hypertension has recently been in the center of attention as Coronavirus Disease 2019 (COVID-19) might lead to acute respiratory distress syndrome associated with hypoxia-induced pulmonary vasoconstriction. Therefore inhalation therapy has been the object of several clinical trials. Purpose In this experimental study we aimed at investigating the hemodynamic effect of inhalative SIN-1a (3-morpholino-syndnonimine, the unstable active metabolite of molsidomine, stabilized by cyclodextrine) administration during physiological and pathological conditions in a large animal model. Methods Landrace pigs were randomized into the following experimental groups: iNO (inhaled nitric-oxide, n=3), SIN-1-5 (5 mg, n=3), SIN-1-10 (10 mg, n=3). Hemodynamic parameters were recorded after parallel insertion of PiCCO system and Swan-Ganz catheter. The effect of iNO and SIN-1 inhalation (30 min) was investigated under physiologic conditions and U46619, a thromboxane-receptor agonist induced pulmonary hypertension. Results The observed alterations after inhalation therapy were quite similar under physiological and pathological condition. Pulmonary arterial pressure (PAP) was decreased by all of these drugs, SIN-1-10 had similar effect as iNO (physiological contidiont: -36.1% iNO, -23.8% SIN-1-5, -35.5% SIN-1-10; U46619-induced pulmonary hypertension: -30.1% iNO, -22.1% SIN-1-5, -31.2% SIN-1-10). While iNO therapy did not influence the mean arterial pressure (MAP) and systemic vascular resistance (SVR) values, SIN-1 administration resulted in decreased MAP and SVR values. Pulmonary vascular resistance (PVR) was decreased by iNO greater than with using SIN-1. As a result of these alterations, the PVR/SVR ratio decreased markedly in the iNO group, while it was stepwisely increased in the SIN-1-5 and SIN-1-10 group. Conclusion The pulmonary vasodilator effect of SIN-1 was dose dependent, and in case of larger dose it was comparable to that of iNO. However, the vasodilatory effects of SIN-1 inhalation was not limited to the pulmonary circulation, a significant and dose-dependent systemic vasodilation could also be documented.

Echocardiographic Assessment of Pulmonary Arterial Hypertension Following Inhaled Nitric Oxide in Infants with Severe Bronchopulmonary Dysplasia

Objectives: Inhaled nitric oxide (iNO) is an effective pulmonary vasodilator. However, the efficacy of iNO in former premature infants with established bronchopulmonary dysplasia (BPD) has not been studied. This study aimed to determine the efficacy of iNO in reducing pulmonary artery pressure in infants with severe BPD as measured by echocardiography. Study Design: Prospective, observational study enrolling infants born at less than 32 weeks gestation and in whom (1) iNO therapy was initiated after admission to our institution, or (2) at the outside institution less than 48 h before transfer and received an echocardiogram prior to iNO initiation, and (3) had severe BPD. Data were collected at three time-points: (1) before iNO; (2) 12–48 h after initiation of iNO; and (3) 48–168 h after initiation of iNO. The primary outcome was the effect of iNO on pulmonary artery pressure measured by echocardiography in patients with severe BPD between 48 and 168 h after initiating iNO therapy. Results: Of 37 enrolled, 81% had echocardiographic evidence of pulmonary arterial hypertension (PAH) before iNO and 56% after 48 h of iNO (p = 0.04). FiO2 requirements were significantly different between time-points (1) and (3) (p = 0.05). There were no significant differences between Tricuspid Annular Plane Systolic Excursion (TAPSE) Z-Scores, time to peak velocity: right ventricular ejection time (TPV:RVET), and ventilator changes. Conclusions: Although we found a statistically significant reduction of PAH between time-point (1) and (3), future trials are needed to further guide clinical care.

The effect of inhaled nitric oxide on shunt fraction in mechanically ventilated patients with COVID-19 pneumonia.

Studies in patients with severe acute respiratory distress syndrome (ARDS) with refractory hypoxaemia suggest that inhaled nitric oxide (iNO) can be added to ventilatory strategies as a potential bridge to clinical improvement. However, the potential role of iNO as a management strategy in severe COVID-19 pneumonia remains unclear. The authors describe their clinical findings of using iNO for severe COVID-19 pneumonia in 10 patients with refractory hypoxaemia in a tertiary respiratory intensive care unit. The results showed an improvement in shunt fraction, P/F ratio, PaO2 and arterial oxygen saturation but the improvements did not translate into a mortality benefit. This report adds to the current body of literature indicating that the correct indications, timing, dose and duration of iNO therapy and how to harness its pleiotropic effects still remain to be elucidated. This brief report adds to the body of literature exploring the potential use of inhaled nitric oxide as a management strategy in patients with severe COVID-19 pneumonia with refractory hypoxaemia. The findings of the report shows that there is a beneficial role of using inhaled nitric oxide to improve respiratory parameters, but that it does not translate to a mortality benefit. It adds to the investigation of establishing which patients, the duration and at what dose, inhaled nitric oxide should be used to gain maximum benefit for this subgroup of patients.

Association between immediate oxygenation response and survival in preterm infants receiving rescue inhaled nitric oxide therapy for hypoxemia from pulmonary hypertension: A systematic review and meta-analysis

PurposeTo investigate whether immediate response to inhaled nitric oxide (iNO) therapy is associated with reduced mortality in preterm infants with hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH). MethodsA systematic review and meta-analysis of observational studies was conducted to examine the association between immediate response (improved oxygenation ≤6 h) compared to non-response, and all-cause mortality among preterm infants <34 weeks gestational age without congenital anomalies or genetic disorders who received iNO treatment. Adjusted and unadjusted odds ratio, were pooled using a random effects meta-analysis Hartung-Knapp-Sidik-Jonkman approach. Subgroup analyses were planned for infants with preterm premature rupture of membranes (PPROM) and those treated within 72 h after birth. ResultsThe primary analysis included 5 eligible studies, a total of 400 infants (196 responders; 204 non-responders). The studies were rated as low to moderate risk of bias based on the Quality in Prognostic Studies tool. Immediate iNO responsiveness was associated with reduced odds of mortality [odds ratio (OR) 0.22, 95 % confidence interval (95 % CI) (0.10–0.49)]. Although there was insufficient data for a subgroup analysis of infants with PPROM, infants treated with iNO within 72 h demonstrated consistent findings of reduced mortality [OR 0.21 95 % CI (0.13–0.36)]. Based on the GRADE approach, considering the risk of bias of included studies, the overall strength of evidence was rated as moderate. ConclusionThere is evidence to suggest that immediate improvement in oxygenation following iNO therapy is associated with reduced odds of mortality before discharge in preterm infants with HRF and clinically suspected or confirmed PH.

Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.

Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy. In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and death at 30 days, 90 days, and 1 year after surgery. Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes. Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO. URL: https://www. gov; Unique identifier: NCT03081052.

Inhaled nitric oxide as rescue therapy in severe ARDS cases due to COVID-19 pneumonia: a single center experience.

Inhaled NO (iNO) has been recommended as rescue therapy in acute respiratory stress syndrome (ARDS) cases. In this study, we aimed to demonstrate the efficacy of iNO as a rescue therapy in patients with severe ARDS due to COVID-19. This retrospective study included patients with ARDS due to COVID-19 who were treated with iNO between March 2020 and January 2022 in the intensive care unit (ICU) of Inonu University. Patients' files were reviewed retrospectively, and demographic data, APACHE II and Sequential Organ Failure Assessment (SOFA) scores, initiation day of iNO and duration of iNO treatment, length of stay in hospital/ICU, blood biochemistry values, complete blood counts, inflammatory parameters, arterial blood gas values, lactate, PaO2/FiO2 ratios, anti-inflammatory drugs and outcome were recorded. Data from 16 patients were reached. iNO was given at a dose of 20 ppm continuously. The mean duration of treatment with iNO was 3.5 days. All patients took the prone position except a single patient. While all patients received steroid therapy, four patients received anti-cytokine therapy, and five patients received intravenous immunoglobulin therapy. All patients were in severe ARDS with a mean PaO2/FiO2 ratio of 58 before iNO therapy. A significant increase in PaO2/FiO2 values was detected with the use of iNO (p<0.05). While three patients (19%) were discharged from the ICU, thirteen patients died. In our study, it was determined that iNO applied as a rescue treatment in patients with severe ARDS improved oxygenation. Although the effect of iNO on survival was low, it may be interpreted as clinically significant considering the severity of the general clinical condition of the patients.

Safety and tolerability of continuous inhaled iloprost in critically ill pediatric pulmonary hypertension patients: A retrospective case series.

Inhaled iloprost (iILO) has shown efficacy in treating patients with hypoxic lung disease and pulmonary hypertension, inducing selective pulmonary vasodilation and improvement in oxygenation. However, its short elimination half-life of 20-30 min necessitates frequent intermittent dosing (6-9 times per day). Thus, the administration of iILO via continuous nebulization represents an appealing method of drug delivery in the hospital setting. The objectives are: (1) describe our continuous iILO delivery methodology and safety profile in mechanically ventilated pediatric pulmonary hypertension patients; and (2) characterize the initial response of iILO in these pediatric patients currently receiving iNO. Continuous iILO was delivered and well tolerated (median 6 days; range 1-94) via tracheostomy or endotracheal tube using the Aerogen® mesh nebulizer system coupled with a Medfusion® 400 syringe pump. No adverse events or delivery malfunctions were reported. Initiation of iILO resulted in an increase in oxygen saturation from 81.4 ± 8.6 to 90.8 ± 4.1%, p < 0.05. Interestingly, prior iNO therapy for >1 day resulted in a higher response rate to iILO (as defined as a ≥ 4% increase in saturations) compared to those receiving iNO <1 day (85% vs. 50%, p = 0.06). When the use of iILO is considered, continuous delivery represents a safe, less laborious alternative and concurrent treatment with iNO should not be considered a contraindication. However, given the retrospective design and small sample size, this study does not allow the evaluation of the efficacy of continuous iILO on outcomes beyond the initial response. Thus, a prospective study designed to evaluate the efficacy of continuous iILO is necessary.