Abnormalities of Coagulation and Fibrinolysis Assessed by Thromboelastometry in an Endotoxic Shock Model in Piglets Treated with Nitric Oxide and Hydrocortisone.

This is an animal model study to investigate changes in hemostasis during endotoxemic shock and to determine whether the combination of inhaled nitric oxide (iNO) + intravenous hydrocortisone had an effect on clot formation and fibrinolysis. iNO selectively decreases pulmonary artery pressure, without affecting cardiac index or systemic vascular resistance; however, the results of studies on the possible consequences of iNO administration on coagulation are inconsistent and require further research. Thirty-four piglets were included. Administering endotoxin caused severe hypodynamic shock. Half of the animals received iNO (30 ppm) + hydrocortisone, starting 3 h after endotoxin infusion and continuing to the end of the study. All animals developed coagulation disorders, manifested by a tendency to hypocoagulation; at the same time, fibrinolysis was impaired. Coagulation and fibrinolysis disorders persisted after endotoxin infusion was discontinued, with worse severity in the animals that died before the study was terminated. Administering iNO + hydrocortisone did not cause further changes in coagulation and fibrinolysis parameters, either during or after the endotoxin challenge, suggesting that potential therapeutic interventions with iNO to lower pulmonary arterial pressure will not affect hemostasis.

Case report: Inhaled nitric oxide rescued a hypoxemia patient caused by dermatomyositis complicated with interstitial pneumonia.

Interstitial pneumonia is the most common and serious secondary lesion of dermatomyositis. In some cases, patients may develop severe acute pneumonia that can quickly progress to respiratory failure, resulting in high mortality rates. A 57-year-old woman with dermatomyositis and interstitial pulmonary fibrosis experienced severe hypoxemia due to pulmonary infection. Despite receiving various treatments after entering the intensive care unit (ICU), such as anti-infection therapy, lung recruitment, prone position ventilation, sedative and muscle relaxation, the patient's oxygen saturation continued to decline. Electrical impedance tomography (EIT) monitoring revealed that prone position could not improve ventilation homogeneity. However, the patient's ventilation/perfusion (V/Q) matching significantly improved 10 min after initiation of supine position ventilation combined with inhalation of nitric oxide (iNO). The patient's PaO2/FiO2 (P/F) ratio increased from 86 mmHg to 150 mmHg at 30 min post-treatment. iNO treatment continued for 2 days. Then the patient's condition improved and she was successfully weaned off the ventilator with rigorous monitoring and symptomatic care. The implementation of mechanical ventilation combined with iNO therapy rapidly improved V/Q matching and oxygenation in a patient with hypoxemia caused by dermatomyositis complicated with interstitial pneumonia. This approach successfully avoided the need for invasive extracorporeal membrane oxygenation (ECMO) support.

Fat embolism syndrome: A severe case diagnosed early using dual-energy CT and saved with VA-ECMO and inhaled nitric oxide.

Diagnosing FES is difficult and time-consuming, and identify FES as an etiology of right ventricular volume overload for early diagnosis. Because FES is a reversible condition, even severe cases can bse treated if the patient survives the acute phase.

High Frequency Oscillatory Ventilation (HFOV) and Inhaled Nitric Oxide (iNO) Use During Neonatal Emergency Transport - Feasibility and Efficacy in India.

A retrospective study of 24 neonates to evaluate the feasibility and efficacy of high frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) for transferring critically ill neonates to tertiary neonatal intensive care, who were transported by road ambulance was done. Efficacy was measured by clinical improvement, patient safety was assessed by comparing cardiorespiratory indicators before and after transport, and adverse events during transport. Significant oxygenation improvement was observed in neonates transported with HFOV ± iNO compared to earlier ventilator settings. Pre- and post-transport vital signs were stable, and no transport-related deaths occurred. A substantial rise in median SpO2 was seen after transfer [86 (81, 91) vs. 93 (89, 97) before transport, p <0.001]. Twelve of twenty-one newborns who received nitric oxide demonstrated significant improvement in oxygenation index (a 10% decrease from prior value). Overall survival was 70.8%, however non-transfer or inadequate respiratory treatment may have exacerbated mortality.

Inhaled NO at a crossroads in cardiac surgery: current need to improve mechanistic understanding, clinical trial design and scientific evidence.

Inhaled nitric oxide (NO) has been used in pediatric and adult perioperative cardiac intensive care for over three decades. NO is a cellular signaling molecule that induces smooth muscle relaxation in the mammalian vasculature. Inhaled NO has the unique ability to exert its vasodilatory effects in the pulmonary vasculature without any hypotensive side-effects in the systemic circulation. In patients undergoing cardiac surgery, NO has been reported in numerous studies to exert beneficial effects on acutely lowering pulmonary artery pressure and reversing right ventricular dysfunction and/or failure. Yet, various investigations failed to demonstrate significant differences in long-term clinical outcomes. The authors, serving as an advisory board of international experts in the field of inhaled NO within pediatric and adult cardiac surgery, will discuss how the existing scientific evidence can be further improved. We will summarize the basic mechanisms underlying the clinical applications of inhaled NO and how this translates into the mandate for inhaled NO in cardiac surgery. We will move on to the popular use of inhaled NO and will talk about the evidence base of the use of this selective pulmonary vasodilator. This review will elucidate what kind of clinical and biological barriers and gaps in knowledge need to be solved and how this has impacted in the development of clinical trials. The authors will elaborate on how the optimization of inhaled NO therapy, the development of biomarkers to identify the target population and the definition of response can improve the design of future large clinical trials. We will explain why it is mandatory to gain an international consensus for the state of the art of NO therapy far beyond this expert advisory board by including the different major players in the field, such as the different medical societies and the pharma industry to improve our understanding of the real-life effects of inhaled NO in large scale observational studies. The design for future innovative randomized controlled trials on inhaled NO therapy in cardiac surgery, adequately powered and based on enhanced biological phenotyping, will be crucial to eventually provide scientific evidence of its clinical efficacy beyond its beneficial hemodynamic properties.

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.

Analysis of Patients with Severe ARDS on VV ECMO Treated with Inhaled NO: A Retrospective Observational Study.

(1) Background: This retrospective study focused on severe acute respiratory distress syndrome (ARDS) patients treated with veno-venous (VV) extracorporeal membrane oxygenation (ECMO) and who inhaled nitric oxide (NO) for pulmonary arterial hypertension (PAH) and/or right ventricular failure (RV failure). (2) Methods: Out of 662 ECMO-supported patients, 366 received VV ECMO, including 48 who inhaled NO. We examined the NO's indications, dosing, duration, and the ability to lower PAH. We compared patients with and without inhaled NO in terms of mechanical ventilation duration, ECMO weaning, organ dysfunction, in-hospital mortality, and survival. (3) Results: Patients received 14.5 ± 5.5 ppm NO for 3 days with only one-third experiencing decreased pulmonary arterial pressure. They spent more time on VV ECMO, had a higher ECMO weaning failure frequency, and elevated severity scores (SAPS II and TIPS). A Kaplan-Meier analysis revealed reduced survival in the NO group. Multiple variable logistic regression indicated a twofold increased risk of death for ARDS patients on VV ECMO with NO. We observed no increase in continuous renal replacement therapy. (4) Conclusions: This study suggests that persistent PAH and/or RV failure is associated with poorer outcomes in severe ARDS patients on VV-ECMO, with an inhaled NO responder rate of only 30%, and it does not impact acute kidney failure rates.

Critical Case of a Preterm Infant Infected With Respiratory Syncytial Virus Managed in the Pediatric Intensive Care Unit: A Case Report.

We describe a critical case of a respiratory syncytial virus (RSV) infection in a preterm infant resulting in respiratory failure with advanced respiratory interventions and discharge from our hospital without the requirement for home oxygen therapy or tube feeding. The infant, delivered at 35 weeks gestation due to a premature rupture of the membranes with a birth weight of 2 kg, initially demonstrated a stable postnatal course. The baby required no resuscitation, with Apgar scores of 8 and 9 at one and five minutes, respectively. The infant was discharged in good condition after four days of hospitalization. This report presents a critical case of RSV infection in a preterm infant requiring intensive care. The infant, born at 35 weeks gestation, initially appeared healthy but developed severe symptoms at 22 days old. The emergency evaluation revealed significant respiratory distress and confirmed RSV pneumonia. Following extensive interventions, including mechanical ventilation to manage severe symptoms, along with complications such as pneumothorax and a cardiac arrest episode, the infant exhibited a positive response to subsequent treatments. The infant responded positively to high-frequency oscillatory ventilation and inhaled nitric oxide. Gradual weaning from advanced ventilation led to successful extubation, followed by recovery with high-flow nasal cannula therapy. The case highlights the challenges of managing severe RSV infections in preterm infants and the efficacy of intensive care interventions in facilitating the infant's remarkable recovery and discharge.

Randomized Controlled Trials of Pulmonary Vasodilator Therapy Adjunctive to Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn: A Systematic Review.

Inhaled nitric oxide (iNO) is a pulmonary vasodilator considered standard of care to treat persistent pulmonary hypertension of the newborn. However, not all infants respond to iNO. The authors performed a systematic review to examine methodology, outcomes, and challenges of randomized controlled trials testing pulmonary vasodilator medications adjunctive to iNO. The 5 trials identified showed heterogeneity in eligibility criteria and outcomes assessed. No trial achieved recruitment goals, limiting conclusions regarding efficacy, safety, and pharmacology. Trial design consensus and alternative methodologic strategies such as deferred consent, real-world controls, nonrandomized database assessments, and Bayesian statistical approaches are needed.

Inhaled Nitric Oxide in Neonatal Pulmonary Hypertension.

Pivotal trials investigating the use of inhaled nitric oxide (iNO) in the 1990s led to approval by the Food and Drug Administration in 1999. Inhaled nitric oxide is the only approved pulmonary vasodilator for persistent pulmonary hypertension of the newborn (PPHN). Selective pulmonary vasodilation with iNO in near-term and term neonates with PPHN is safe, and targeted use of iNO in less mature neonates with pulmonary hypertension (PH) can be beneficial. This review addresses a brief history of iNO, clinical features of neonatal PH, and the clinical application of iNO.

The effect of inhaled nitric oxide on maximal oxygen consumption during exercise in acute hypoxia: a randomized double-blind crossover trial.

In moderate hypoxia [partial pressure of inspired oxygen ([Formula: see text]) = 85-111 mmHg], the reduction in maximal oxygen consumption (V̇o2max) has been attributed to arterial desaturation, whereas in severe hypoxia ([Formula: see text] < 85 mmHg), elevated pulmonary artery pressure (PAP) is thought to impair peak cardiac output ([Formula: see text]) and therefore V̇o2max. The purpose of this study was to examine whether reducing PAP with inhaled nitric oxide (iNO, a selective pulmonary vasodilator) would increase V̇o2max in moderate and severe acute hypoxia. Twelve young, healthy participants (mean V̇o2max = 45.3 ± 12.2 mL/kg/min), with normal lung function completed the randomized double-blind crossover study over six sessions. Experimental cardiopulmonary exercise tests (CPET) were completed on separate days with participants under the following conditions: 1) acute moderate hypoxia ([Formula: see text] = 89 mmHg), 2) acute severe hypoxia ([Formula: see text] = 79 mmHg), 3) acute moderate hypoxia with 40 ppm iNO, and 4) acute severe hypoxia with 40 ppm iNO (order randomized). On separate days, rest, and exercise (60 W), echocardiography was conducted to determine right ventricular systolic pressure (RVSP/PAP) under conditions 1-4. Resting RVSP was reduced by 2.5 ± 0.8 mmHg with iNO in moderate hypoxia (P = 0.01) and 1.8 ± 0.2 mmHg in severe hypoxia (P = 0.05); however, iNO had no effect on peak [Formula: see text] or V̇o2max in either hypoxic condition. Despite reducing RVSP with iNO in hypoxia, peak [Formula: see text] and V̇o2max were unaffected, suggesting that iNO may not improve exercise tolerance in healthy participants during hypoxic exercise.NEW & NOTEWORTHY The elevation of pulmonary artery pressure (PAP) with hypoxia may impair peak cardiac output ([Formula: see text]) and therefore V̇o2max. Our novel findings show that despite reducing resting RVSP in acute moderate ([Formula: see text] = 89 mmHg) and severe hypoxia ([Formula: see text] = 79 mmHg) with inspired nitric oxide, peak [Formula: see text], and V̇o2max were unaffected.

Inhaled Pulmonary Vasodilators for the Treatment of Right Ventricular Failure in Cardio-Thoracic Surgery: Is One Better than the Others?

Right ventricular failure (RFV) is a potential complication following cardio-thoracic surgery, with an incidence ranging from 0.1% to 30%. The increase in pulmonary vascular resistance (PVR) is one of the main triggers of perioperative RVF. Inhaled pulmonary vasodilators (IPVs) can reduce PVR and improve right ventricular function with minimal systemic effects. This narrative review aims to assess the efficacy of inhaled nitric oxide and inhaled prostacyclins for the treatment of perioperative RVF. The literature, although statistically limited, supports the clinical similarity between them. However, it failed to demonstrate a clear benefit from the pre-emptive use of inhaled nitric oxide in patients undergoing left ventricular assist device implantation or early administration during heart-lung transplants. Additional concerns are related to cost safety and IPV use in pathologies associated with pulmonary venous congestion. The largest ongoing randomized controlled trial on adults (INSPIRE-FLO) is addressing whether inhaled Epoprostenol and inhaled nitric oxide are similar in preventing RVF after heart transplants and left ventricular assist device placement, and whether they are similar in preventing primary graft dysfunction after lung transplants. The preliminary analysis supports their equivalence. Several key points may be achieved by the present narrative review. When RVF occurs in the setting of elevated PVR, IPV should be the preferred initial treatment and they should be preventively used in patients at high risk of postoperative RVF. If severe refractory postoperative RVF occurs, IPVs should be combined with complementary pharmacology (inotropes and inodilators). If unsuccessful, right ventricular mechanical support should be established.

Real-world safety and effectiveness of inhaled nitric oxide therapy for pulmonary hypertension during the perioperative period of cardiac surgery: a post-marketing study of 2817 patients in Japan.

OBJECTIVE: To evaluate the real-world safety and effectiveness of inhaled nitric oxide (INOflo® for Inhalation 800 ppm) for perioperative pulmonary hypertension associated with cardiac surgery in Japan. METHODS: This was a prospective, non-interventional, all-case, post-marketing study of pediatric and adult patients who received perioperative INOflo with cardiac surgery from November 2015-December 2020. Safety and effectiveness were monitored from INOflo initiation to 48 h after treatment completion or withdrawal. Safety outcomes included adverse drug reactions, blood methemoglobin concentrations, and inspired nitrogen dioxide concentrations over time. Effectiveness outcomes included changes in central venous pressure among pediatrics, mean pulmonary arterial pressure among adults, and the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (PaO2/FiO2) in both populations. RESULTS: The safety analysis population included 2,817 Japanese patients registered from 253 clinical sites (pediatrics, n = 1375; adults, n = 1442). INOflo was generally well tolerated; 15 and 20 adverse drug reactions were reported in 14 pediatrics (1.0%) and 18 adults (1.2%), respectively. No clinically significant elevations in blood methemoglobin and inspired nitrogen dioxide concentrations were observed. INOflo treatment was associated with significant reductions in both central venous pressure among pediatrics and mean pulmonary arterial pressure among adults, and significant improvements in PaO2/FiO2 among pediatrics and adults with PaO2/FiO2 ≤ 200 at baseline. CONCLUSIONS: Perioperative INOflo treatment was a safe and effective strategy to improve hemodynamics and oxygenation in patients with pulmonary hypertension during cardiac surgery. These data support the use of INOflo for this indication in Japanese clinical practice.

Treating very preterm European infants with inhaled nitric oxide increased in-hospital mortality but did not affect neurodevelopment at 5 years of age.

AIM: We examined the outcomes of using inhaled nitric oxide (iNO) to treat very preterm born (VPT) infants across Europe. METHODS: This was a sub-study of the Screening to Improve Health in Very Preterm Infants in Europe research. It focused on all infants born between 22 + 0 and 31 + 6 weeks/days of gestation from 2011 to 2012, in 19 regions in 11 European countries. We studied 7268 infants admitted to neonatal care and 5 years later, we followed up the outcomes of 103 who had received iNO treatment. They were compared with 3502 propensity score-matched controls of the same age who did not receive treatment. RESULTS: All countries used iNO and 292/7268 (4.0%) infants received this treatment, ranging from 1.2% in the UK to 10.5% in France. There were also large regional variations within some countries. Infants treated with iNO faced higher in-hospital mortality than matched controls (odds ratio 2.03, 95% confidence interval 1.33-3.09). The 5-year follow-up analysis of 103 survivors showed no increased risk of neurodevelopmental impairment after iNO treatment. CONCLUSION: iNO was used for VPT patients in all 11 countries. In-hospital mortality was increased in infants treated with iNO, but long-term neurodevelopmental outcomes were not affected in 103 5-year-old survivors.

The early use of inhaled nitric oxide in premature infants requiring respiratory support.

Background: Earlier studies on the use of inhaled nitric oxide (iNO) for premature infants born at <34 weeks of gestation requiring respiratory support did not provide conclusive evidence of benefit. National guidelines generally discouraged the use in this population. More recent national guidelines endorsed the use of iNO in premature infants with hypoxic respiratory failure (HRF) associated with persistent pulmonary hypertension of the newborn (PPHN).Recent Studies: Two recently published observational studies evaluated the effect of administering iNO on oxygenation in the first week of life. These studies compared premature infants born at the gestational age (GA) of <34 weeks with HRF associated with PPHN to term and late preterm infants born at the GA of ≥34 weeks who received iNO. Both studies showed a similar effect of iNO on oxygenation in the two infant cohorts. The response rate in the premature infant cohort was 59% in the first study and 90% in the second. The mean response time was 9.2 h and 10.3 h, and the mean duration of therapy was 3.5 days and 8.2 days, respectively.Conclusion: The results of these studies support a trial of iNO in premature infants with persistent hypoxia despite optimum respiratory support. Obtaining a timely echocardiogram to exclude cardiac diseases and diagnose PPHN is logistically challenging for many clinicians, thus, a clinical diagnosis of PPHN might have to be made in these situations. Questions remain regarding the optimum dose of iNO and the duration of the initial iNO trial in these patients.KEY MESSAGESIn the most recently published studies, the improvement of oxygenation in iNO-treated infants born at <34 weeks of gestation with HRF and PPHN physiology was as effective as in infants born ≥34 weeks.These studies provide evidence supporting a trial of iNO in the subpopulation of premature infants with HRF associated with PPHN.

Can Inhaled Nitric Oxide Response Predict Tolerance to Therapies and Survival in Patients With Combined Precapillary and Postcapillary Pulmonary Hypertension?

Inhaled nitric oxide (iNO) relaxes the pulmonary circulation and variably increases the left ventricular preload and pulmonary artery wedge pressure (PAWP)-hemodynamic information that may help guide treatment decisions and assess prognosis in patients with combined precapillary and postcapillary pulmonary hypertension (PH). We included consecutive patients with combined precapillary and postcapillary PH (mean pulmonary artery pressure >20 mm Hg, PAWP >15 mm Hg, and pulmonary vascular resistance [PVR] >2 Woods unit [WU]) who underwent right-sided cardiac catheterization with iNO at the Cleveland Clinic Pulmonary Vascular Disease program between 2017 and 2022. We included 104 patients with baseline PAWP and PVR of 22.2 ± 4.2 mm Hg and 6.1 ± 3.2 WU, respectively. Pulmonary arterial hypertension (PAH) with postcapillary component and PH left heart disease with precapillary component were identified in 27 (26%) and 77 patients (74%), respectively. No side effects were noted during the administration of iNO. During iNO, the PVR decreased 1.1 ± 1.4 WU and the PAWP increased 1.3 ± 3.7 mm Hg. A more pronounced increase in PAWP with iNO was associated with a decrease in PVR (R -0.35, p <0.001) and increase in stroke volume (R 0.20, p = 0.046). Tolerance to PAH-specific medications, overall survival, and heart failure hospitalizations were not significantly associated with the change in PAWP or PVR with iNO. In conclusion, in patients with combined precapillary and postcapillary PH, iNO challenge is safe and caused a significant decrease in PVR, with an increase in PAWP. The changes in PAWP and PVR during iNO administration were not associated with tolerance to PAH-specific medications, heart failure-related hospitalization, or survival.

Inhaled nitric oxide: can it serve as a savior for COVID-19 and related respiratory and cardiovascular diseases?

Nitric oxide (NO), as an important gaseous medium, plays a pivotal role in the human body, such as maintaining vascular homeostasis, regulating immune-inflammatory responses, inhibiting platelet aggregation, and inhibiting leukocyte adhesion. In recent years, the rapid prevalence of coronavirus disease 2019 (COVID-19) has greatly affected the daily lives and physical and mental health of people all over the world, and the therapeutic efficacy and resuscitation strategies for critically ill patients need to be further improved and perfected. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator, and some studies have demonstrated its potential therapeutic use for COVID-19, severe respiratory distress syndrome, pulmonary infections, and pulmonary hypertension. In this article, we describe the biochemistry and basic characteristics of NO and discuss whether iNO can act as a "savior" for COVID-19 and related respiratory and cardiovascular disorders to exert a potent clinical protective effect.

Outcome of obstructed total anamalous pulmonary venous connection (TAPVC) repair patients with milrinone versus milrinone and inhaled nitric oxide (INO): A prospective randomized observational study.

Background: Obstructed total anomalous pulmonary venous connection (TAPVC) typically present with severe cardiovascular decompensation and requires urgent surgical management. Pulmonary arterial hypertension (PAH) is a major risk factor affecting mortality. Perioperative management focuses on providing inotropic support and managing potential pulmonary hypertensive episodes. Milrinone and inhaled nitric oxide (iNO) efficiently reduce pulmonary artery pressure (PAP) and help to improve the outcome. The aim was to determine the outcome of patients with high PAP with milrinone alone and a combination of iNO and milrinone. Material and Method: After ethical committee approval, the study was conducted over a period of 3 years in 80 patients with obstructed TAPVC repair. A total of 80 patients having severe PAH (supra systemic arterial pressure) randomly divided into two groups with 40 patients in each (M & MN). Group M (milrinone) patients received milrinone and Group MN (milrinone & iNO) patients received both milrinone (after opening aortic cross clamp) and iNO (post operative ICU). Ventilation time, hospital stay, ICU stay, complications, in hospital mortality were compared between both groups. Result: Ventilation time, Intensive Care Unit (ICU) stay, hospital stay for group M was 8.02 ± 5.74 days, 11.25 ± 7.33 day, 14.92 ± 8.55 days, respectively, and for group MN was 5.02 ± 1.78 days, 8.27 ± 3.24 days, 10.3 ± 3.18 days, respectively. In hospital mortality for group M and MN was 10% and 2.5%, respectively. P value for each variable was significant < 0.05 (except mortality). Conclusion: Most of the patients with obstructed TAPVC had severe PAH. Management of severe PAH with a combination of milrinone with iNO had a better outcome than milrinone alone.

Inhaled nitric oxide testing in predicting prognosis in pulmonary hypertension due to left-sided heart diseases.

AIMS: The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. METHODS AND RESULTS: This was a single-centre, retrospective study with a median follow-up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. CONCLUSIONS: Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.