Selective Pulmonary Vasodilator Research Articles

MELHORES ELEIÇÕES PARA DIAGNÓSTICO E TRATAMENTO DA HIPERTENSÃO PULMONAR ASSOCIADA A DOENÇA CARDÍACA ESQUERDA

Pulmonary hypertension associated with left heart disease (PH-LHD) is the most prevalent form of pulmonary hypertension, affecting patients with heart failure and valvular disease. Divided into isolated post-capillary and combined pre-capillary, PH-LHD is characterized by a challenging prognosis, due to the difficulty in identifying the factors that contribute to its progression. Early diagnosis is essential and can be aided by imaging tests and procedures such as cardiac catheterization, with volume testing being an important tool to differentiate the types of PH. The management of PH-LHD involves symptom control and treatment of the underlying heart failure. Although there are no specific therapies to significantly improve the prognosis, diuretics and selective pulmonary vasodilators are used, with surgical interventions in more severe cases. Recent research has investigated treatments such as phosphodiesterase-5 inhibitors, which have shown some hemodynamic improvement, and pulmonary artery denervation, a promising technique, but still in the investigational phase. Despite advances, PH-DCE remains associated with high mortality, especially in patients with progressive elevation of pulmonary vascular resistance. Treatment should focus on managing underlying cardiac diseases and seeking new therapeutic approaches.

Effects of sildenafil on gas exchange, ventilatory, and sensory responses to exercise in subjects with mild-to-moderate COPD: A randomized cross-over trial

Excess exercise ventilation (high ventilation (V̇E)/carbon dioxide output (V̇CO2)) contributes significantly to dyspnea and exercise intolerance since the earlier stages of chronic obstructive pulmonary disease (COPD). A selective pulmonary vasodilator (inhaled nitric oxide) has shown to increase exercise tolerance secondary to lower V̇E/V̇CO2 and dyspnea in this patient population. We aimed to assess whether a clinically more practical option - oral sildenafil - would be associated with similar beneficial effects. In a randomized, placebo-controlled study, twenty-four patients with mild-to-moderate COPD completed, on different days, two incremental cardiopulmonary exercise tests (CPET) one hour after sildenafil or placebo. Eleven healthy participants performed a CPET in a non-interventional visit for comparative purposes with patients when receiving placebo. Patients (FEV1= 69.4 ± 13.5 % predicted) showed higher ventilatory demands (V̇E/V̇CO2), worse pulmonary gas exchange, and higher dyspnea during exercise compared to controls (FEV1= 98.3 ±11.6 % predicted). Contrary to our expectations, however, sildenafil (50 mg; N= 15) did not change exertional V̇E/V̇CO2, dead space/tidal volume ratio, operating lung volumes, dyspnea, or exercise tolerance compared to placebo (P>0.05). Due to the lack of significant beneficial effects, nine additional patients were trialed with a higher dose (100 mg). Similarly, active intervention was not associated with positive physiological or sensory effects. In conclusion, acute oral sildenafil (50 or 100 mg) failed to improve gas exchange efficiency or excess exercise ventilation in patients with predominantly moderate COPD. The current study does not endorse a therapeutic role for sildenafil to mitigate exertional dyspnea in this specific patient subpopulation.Clinical trial registry: https://ensaiosclinicos.gov.br/rg/RBR-4qhkf4Web of Science Researcher ID: O-7665–2019

Evaluation of Inhaled Nitric Oxide Generation Systems at Altitude.

Inhaled nitric oxide (INO) is a selective pulmonary vasodilator delivered from compressed gas cylinders filled to 2,200 psig (137.8 bar) with 800 ppm of NO in a balance of nitrogen. NO is currently FDA-approved for use in term or near-term infants with hypoxemia and signs of pulmonary hypertension in the absence of cardiac disease. INO has also been shown to improve oxygenation in adults with refractory hypoxemia. Current doctrine precludes the use of NO during military aeromedical transport owing to the requirement for large compressed gas cylinders. We performed a bench evaluation of 2 delivery systems that create NO from room air without the need for pressurized cylinders. We evaluated 2 portable nitric oxide INO generation systems (LungFit PH, Beyond Air Inc, Garden City, NJ and a prototype NO generator, Odic Inc, Littleton, MA) at ground level, 8,000, and 14,000 feet (2,437 and 4,267 meter) simulated altitude in an altitude chamber. The output from each device was injected into the inspiratory limb of the ventilator circuit that was attached to a test lung. A 731 ventilator (Zoll Medical, Chelmsford, MA) and T1 (Hamilton Medical, Reno, NV) were used employing 24 combinations of ventilator settings each repeated in duplicate. An INOmax DS IR was used to measure delivered INO and NO2 via a sampling line attached in the ventilator circuit inspiratory limb. A fast response oxygen analyzer (O2CAP, Oxigraf Inc, Sunnyvale, CA) was used to measure inspired FiO2. Target INO concentration was 20 ppm. Across all ventilator settings, the LungFit device delivered INO was 19.8 ± 1.6 ppm, 16.1 ± 1.9 ppm, and 11.6 ± 1.7 ppm at ground level, 8,000 ft (2,437 meter), and 14,000 ft (4,267 meter), respectively. The Odic device delivered INO dose was 20.6 ± 1.4 ppm, 21.3 ± 5.5 ppm, and 20.4 ± 9.1 ppm at ground level, 8,000 ft (2,437 meter), and 14,000 ft (4,267 meter), respectively. Both devices delivered a reliable INO dose at ground level. Altitude significantly affected INO delivery accuracy at 14,000 ft (4,267 meter) (P < 0.01) with both devices and at 8,000 ft (2,437 meter) (P < 0.01) with LungFit. Differences in INO dosage were not statistically significant with the Odic device at 8,000 ft (2,437 meter)(P > 0.05) although there were large variations with selected ventilator settings. With careful monitoring, devices creating INO from room air without cylinders could be used during aeromedical transport without the need for pressurized cylinders.

Pulmonary vasodilation during cardiopulmonary resuscitation – A randomized, controlled porcine study

BackgroundDuring resuscitation pulmonary artery pressure (PAP) increases. This reduces left ventricular filling, leading to decreased blood flow. Inhaled nitric oxide (iNO) produces selective pulmonary vasodilation. We hypothesized that iNO would lower PAP during resuscitation resulting in increased survival. Methods30 pigs (40 kg) were subjected to cardiac arrest for 9.5 min after myocardial ischemia induced by coronary artery occlusion of the left anterior descending artery and ventricular fibrillation. During resuscitation, the pigs were randomized to 40 ppm iNO or placebo. The primary outcome was return of spontaneous circulation (ROSC). Pigs achieving ROSC underwent 4-hours intensive care. ResultsThe ROSC rate was 9/14 (64%) in the control group and 11/16 (69%) in the iNO group (OR 1.2 95%CI [0.3;5.6], p > 0.99). There was no difference in diastolic aorta pressure/PAP ratio (mean difference −0.99 [95% CI: −2.33–0.36], p = 0.14). Mean pulmonary artery pressure was lower in the iNO group 60 and 120 min after ROSC (mean difference: −12.18 mmHg [95%CI: −16.94; −7.43] p < 0.01 and −5.43 [95%CI: −10.39; −0.46] p = 0.03). Troponin I levels in the iNO group were significantly higher 60 and 120 min after ROSC (mean difference: 266105 ng/l [95%CI: 6356; 525855] p = 0.045 and 420049 ng/l [95%CI: 136779; 703320], p = 0.004). The area at risk of the heart was 33% (SD 1) in controls and 34% (SD 1) in the iNO group. The infarct size divided by the area at risk was 55% (SD 3) in controls and 86% (SD 1) in the iNO group, p = 0.01. ConclusionApplication of iNO did not improve the rate of ROSC or hemodynamic function but increased myocardial injury.

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.

A novel, cassette-based nitric oxide delivery system with an advanced feedback control algorithm accurately delivers nitric oxide via the anesthesia machine independent of fresh gas flow rate and volatile anesthetic agent

Nitric oxide (NO), a selective pulmonary vasodilator, can be delivered via conventional ICU and anesthesia machine ventilators. Anesthesia machines are designed for rebreathing of circulating gases, reducing volatile anesthetic agent quantity used. Current cylinder- and ionizing-based NO delivery technologies use breathing circuit flow to determine NO delivery and do not account for recirculated gases; therefore, they cannot accurately dose NO at FGF below patient minute ventilation (MV). A novel, cassette-based NO delivery system (GENOSYL® DS, Vero Biotech Inc.) uses measured NO concentration in the breathing circuit as an input to an advanced feedback control algorithm, providing accurate NO delivery regardless of FGF and recirculation of gases. This study evaluated GENOSYL® DS accuracy with different anesthesia machines, ventilation parameters, FGFs, and volatile anesthetics. GENOSYL® DS was tested with GE Aisys and Dräger Fabius anesthesia machines to determine NO dose accuracy with FGF < patient MV, and with a Getinge Flow-i anesthesia machine to determine NO dose accuracy when delivering various volatile anesthetic agents. Neonatal and adult mechanical ventilation parameters and circuits were used. GENOSYL® DS maintained accurate NO delivery with all three anesthesia machines, at low FGF with recirculation of gases, and with all volatile anesthetic agents at different concentrations. Measured NO2 levels remained acceptable at ≤ 1 ppm with set NO dose ≤ 40 ppm. GENOSYL® DS, with its advanced feedback control algorithm, is the only NO delivery system capable of accurately dosing NO with anesthesia machines with rebreathing ventilation parameters (FGF < MV) regardless of anesthetic agent.

Changes in Inhaled Nitric Oxide Use Across ICUs After Implementation of a Standard Pathway.

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator. It is expensive, frequently used, and not without risk. There is limited evidence supporting a standard approach to initiation and weaning. Our objective was to optimize the use of iNO in the cardiac ICU (CICU), PICU, and neonatal ICU (NICU) by establishing a standard approach to iNO utilization. A quality improvement study using a prospective cohort design with historical controls. Four hundred seven-bed free standing quaternary care academic children's hospital. All patients on iNO in the CICU, PICU, and NICU from January 1, 2017 to December 31, 2022. Unit-specific standard approaches to iNO initiation and weaning. Sixteen thousand eighty-seven patients were admitted to the CICU, PICU, and NICU with 9343 in the pre-iNO pathway era (January 1, 2017 to June 30, 2020) and 6744 in the postpathway era (July 1, 2020 to December 31, 2022). We found a decrease in the percentage of CICU patients initiated on iNO from 17.8% to 11.8% after implementation of the iNO utilization pathway. We did not observe a change in iNO utilization between the pre- and post-iNO pathway eras in either the PICU or NICU. Based on these data, we estimate 564 total days of iNO (-24%) were saved over 24 months in association with the standard pathway in the CICU, with associated cost savings. Implementation of a standard pathway for iNO use was associated with a statistically discernible reduction in total iNO usage in the CICU, but no change in iNO use in the NICU and PICU. These differential results likely occurred because of multiple contextual factors in each care setting.

Novel inhaled pulmonary vasodilators in adult cardiac surgery: a scoping review.

Pulmonary hypertension (PH) is a common cause of postoperative mortality in cardiac surgery that is commonly treated with conventional inhaled therapies, specifically nitric oxide and prostacyclin. Alternative therapies include inhaled milrinone and levosimendan, which are receiving more research interest and are increasing in clinical use as they may cut costs while allowing for easier administration. We sought to conduct a scoping review to appraise the evidence base for the use of these two novel inhaled vasodilators as an intervention for PH in cardiac surgery. We searched Embase and MEDLINE for relevant articles from 1947 to 2022. We identified 17 studies including 969 patients. The included studies show that inhaled milrinone and levosimendan are selective pulmonary vasodilators with potential benefits ranging from ease of weaning from cardiopulmonary bypass to reduction in ventricular dysfunction. Nevertheless, high-quality data are limited, and study design and comparators are extremely heterogeneous, limiting the potential validity and generalizability of findings. The findings of this scoping review suggest that milrinone and levosimendan may be effective alternatives to current inhaled therapies for cardiac dysfunction in the setting of PH. Nevertheless, randomized trials have focused on specific agents and consistent outcome measures are needed to better validate the early-stage promise of these agents. Open Science Framework ( https://osf.io/z3k6f/ ); first posted 21 July 2022.

Neurophysiological Mechanisms of Exertional Dyspnea in Patient’s Post-Pulmonary Embolism: The Effect of Inhaled Nitric Oxide

Following pulmonary embolism (PE), up to a third of patients develop persistent activity-related dyspnea, even in those without chronic thromboembolic pulmonary hypertension (CTEPH). It has been shown that heightened exertional dyspnea in patients post-PE (without CTEPH) is linked to greater inspiratory neural drive (IND) during exercise. The heightened IND, in turn, is secondary to increased physiological dead space (VD/VT) and greater ventilatory requirements for CO2 (VE/VCO2). The reasons for the increased VD/VT and VE/VCO2 are unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Thus, the current study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower exertional IND and dyspnea, and improve exercise endurance in patients post-PE. In turn, the reduced IND and dyspnea would be linked to reductions in VD/VT and VE/VCO2. In this randomized, double-blind, placebo-controlled crossover study, 14 clinically stable patients with chronic activity related dyspnea post-PE (without evidence of PH) completed symptom-limited constant work rate cycle exercise tests while breathing iNO (40 ppm) or placebo (21% O2), on separate days. IND (assessed by diaphragm electromyography), VD/VT and VE/VCO2 (expired and arterialized blood gas), and dyspnea intensity (modified Borg 0-10 scale) were compared throughout exercise. At rest, right-ventricular systolic pressure (RVSP) with placebo or iNO was estimated by echocardiography. At the highest individual standardized exercise time (5.8±2.0 min), iNO decreased VD/VT (0.22±0.09 vs 0.27±0.07, p=0.02), VE/VCO2 (33.0±3.5 vs 34.5±3.8 units, p=0.04), IND (48.8±10.3 vs 57.6±11.8 %, p=0.02) and dyspnea intensity (3.0±1.0 vs 4.0±1.4 Borg units, p&lt;0.01), compared with placebo. Throughout exercise, estimated alveolar ventilation, O2 saturation, O2 pulse and operating lung volumes were unaffected by iNO (all p&gt;0.05). iNO increased exercise endurance time (8.1±3.5 vs 6.5±2.3 min, p&lt;0.001), compared with placebo. iNO reduced resting RVSP by 2.5±2.0 mmHg. iNO decreased exertional IND and dyspnea, and improved exercise endurance in patients with post-PE. The reduced IND, in turn, may be linked to decreased VD/VT and VE/VCO2, reflecting improved ventilation/perfusion. These data provide preliminary evidence of a partially reversible pulmonary vasculopathy, that contributes to dyspnea and exercise limitation in symptomatic patients post-PE. Queen’s University Spear Endowment Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Safety of inhaled nitric oxide withdrawal in severe chronic pulmonary hypertension.

Inhaled nitric oxide (iNO) is a potent and selective pulmonary vasodilator with a safety concern due to rebound pulmonary hypertension (PH) associated with its withdrawal. We report short-term pulsed iNO in patients with severe pulmonary arterial hypertension (PAH) and nonoperable chronic thromboembolic PH (nCTEPH). This is a retrospective analysis of 33 patients: 22 with PAH and 11 with nCTEPH. We assessed hemodynamic, echocardiographic, and other noninvasive variables to evaluate safety and efficacy of iNO. We performed an iNO withdrawal test during right heart catheterization and after 3 days of iNO treatment. iNO significantly improved all variables examined in 22 patients with PAH and 11 with nCTEPH. Two patterns of response were observed after sudden iNO withdrawal. Twenty-nine patients (88%) showed minimal hemodynamic, oxygenation and clinical changes. Four patients (12%) had a reduction in cardiac index ≥20% and PaO2 ≥ 5%, three patients did not show clinical deterioration, and one patient developed hemodynamic collapse that needed iNO administration. This retrospective study suggests that short-term iNO improves hemodynamics and clinical conditions in some patients with PAH an nCTPEH. However, pulsed iNO withdrawal PH rebound could be a serious concern in these patients. Given the lack of evidence, we do not recommend the use of pulsed iNO in the treatment of patients with chronic PH.

ЛЕЧЕНИЕ ЛЕГОЧНОЙ ГИПЕРТЕНЗИИ У ПАЦИЕНТОВ С СЕРПОВИДНОКЛЕТОЧНОЙ АНЕМИЕЙ С ИСПОЛЬЗОВАНИЕМ СИЛДЕНАФИЛА

Pulmonary hypertension is a common complication of sickle cell disease associated with hemolysis, impaired bioavailability of nitric oxide, and high mortality. The aim of the study is to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative drugs in this risk group. Materials and methods. After optimizing sickle cell therapy to stabilize fetal hemoglobin levels, we evaluated the safety and efficacy of sildenafil in 9 patients with sickle cell disease and pulmonary hypertension. Results. Sildenafil therapy (mean duration 6 ± 1 month) reduced estimated pulmonary systolic pressure [50 ± 4-41 ± 3 mmHg; 9 mmHg difference, 95% confidence interval (CI): 0.3-17, P = 0.043] and increased the 6-minute walking distance (384 ± 30 to 462 ± 28 m; 78 m difference, 95% CI: 40-117, P = 0.0012). Transient headaches were observed in two patients and transient eyelid edema in four patients. The three men in the study did not have any episodes of priapism. Two of them received chronic exchange transfusions, and one had erectile dysfunction. Conclusions. Patients with sickle cell disease and pulmonary hypertension have significant limitations in physical activity. Walking for 6 minutes may be a valid endpoint in this population. Sildenafil therapy is safe and improves pulmonary hypertension and physical performance. Additional phase I studies in men with sickle cell disease are needed, followed by a placebo-controlled phase II/III to evaluate the safety and efficacy of sildenafil therapy in patients with sickle cell disease and pulmonary hypertension.

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.

Study of the Acute Hemodynamic Effects of Inhaled Milrinone versus Inhaled Nitroglycerin on Mechanically Ventilated Patients with Pulmonary Hypertension after Mitral Valve Replacement Surgeries

Abstract Background Pulmonary hypertension is a usual complication of long-standing mitral valve disease. Perioperative pulmonary hypertension is a risk factor for right ventricular failure and is an important cause of morbidity and mortality in patients with pulmonary hypertension undergoing mitral valve surgery. Aim of the Work To compare inhaled milrinone and inhaled nitroglycerin hemodynamic effects on mechanically ventilated patients with pulmonary hypertension after mitral valve replacement surgery by measuring invasive blood pressure, heart rate, central venous pressure and bedside transthoracic echocardiography to assess pulmonary artery pressure. Patients and Methods The study was conducted in National Heart Institute, Giza, Egypt during the six months between October, 2020 and March, 2021. This study was conducted on 40 patients. Patients were randomized on the basis of computer-generated random numbers into two equal groups (20 patients each) Using PASS11 program for sample size calculation. In group A, patients received inhaled nitroglycerin (50 µ/kg) and in group B, patients received inhaled milrinone (50 µ/kg) through jet nebulizer. Results Both inhaled milrinone and inhaled nitroglycerin proved to be selective pulmonary vasodilators, since they induced significant reductions in mPAP, SPAP, and DPAP. The favorable effects of both agents on the pulmonary vasculature was confirmed by both hemodynamic and echocardiographic measurements. At the same time, both agents were devoid of systemic side effects, since mean arterial pressure, systolic arterial pressure and diastolic arterial pressure were not affected. Conclusion There was no significance between two groups, so inhaled nitroglycerin appears to be an effective, easy to administer, inexpensive, available and save alternative for treatment of PH in mechanically ventilated patients after mitral valve replacement surgeries as there was no significance between two groups.

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.

Inhaled nitric oxide use in newborns.

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, is used as a therapeutic modality in infants with hypoxemic respiratory failure (HRF) associated with persistent pulmonary hypertension of the newborn (PPHN). iNO should ideally be initiated following echocardiographic confirmation of PPHN. Use of iNO is recommended in late preterm and term infants who develop HRF despite optimal oxygenation and ventilation strategies. However, routine iNO use in preterm infants on respiratory support is not recommended. iNO may be considered as a rescue modality in preterm infants with early-onset HRF when associated with prolonged rupture of membranes or oligohydramnios, or late-onset HRF in the context of bronchopulmonary dysplasia-associated pulmonary hypertension (PH) with severe right ventricular failure. A trial of iNO may also be considered for infants with congenital diaphragmatic hernia with persistent HRF despite optimal lung recruitment, and with echocardiographic evidence of supra-systemic PH and adequate left ventricular function.

An electrochemical nitric oxide generator for in-home inhalation therapy in pulmonary artery hypertension

BackgroundInhaled NO is a selective pulmonary vasodilator proven to be therapeutic for patients with pulmonary artery hypertension (PAH). The most common NO delivery system in clinical practice is cylinder-based, but unfortunately limited by its high costs, complicated delivery, and the requirement of an extensive supply chain, leaving vast unmet medical needs globally.MethodsTo address the need for rapid, affordable, and safe production of nitric oxide (NO) for in-home inhalation therapy in patients with PAH. We developed a novel portable device to derive NO from a nitrite complex solution with a copper(II)-ligand catalyst, and further examined its effectiveness in a porcine model of PAH. This model was established by using female Bama miniature pig and induced by monocrotaline (MCT) administration.ResultsThis generator could rapidly and safely produce therapeutic NO at concentrations ranging from 0 to 100 parts per million (ppm) with the least disproportionated nitrogen dioxide (NO2) and byproducts. It could effectively alleviate pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in piglets with PAH, without causing major physiologic disruptions.ConclusionsOur electrochemical NO generator is able to produce the desired NO doses for pulmonary vasodilation in a safe and sustainable way, with low costs, which paves the way for its subsequent clinical trials in the patient with PAH and other common cardiopulmonary conditions with a high disease burden around the world.

The differential roles of the two NO-GC isoforms in adjusting airway reactivity.

The enzyme, nitric oxide-sensitive guanylyl cyclase (NO-GC), is activated by binding NO to its prosthetic heme group and catalyzes the formation of cGMP. The NO-GC is primarily known to mediate vascular smooth muscle relaxation in the lung, and inhaled NO has been successfully used as a selective pulmonary vasodilator. In comparison, NO-GC's impact on the regulation of airway tone is less acknowledged and, most importantly, little is known about the issue that NO-GC signaling is accomplished by two isoforms: NO-GC1 and NO-GC2, implying the existence of distinct "cGMP pools." Herein, we investigated the functional role of the NO-GC isoforms in respiration by measuring lung function parameters of isoform-specific knockout (KO) mice using noninvasive and invasive techniques. Our data revealed the participation and ongoing influence of NO-GC1-derived cGMP in the regulation of airway tone by showing that respiratory resistance was enhanced in NO-GC1-KOs and increased more pronouncedly after the challenge with the bronchoconstrictor methacholine. The tissue resistance and stiffness of NO-GC1-KOs were also higher because of narrowed airways that cause tissue distortion. Contrariwise, NO-GC2-KOs displayed reduced tissue elasticity, elastic recoil, and airway reactivity to methacholine, which did not even increase in an ovalbumin model of asthma that induced hyperresponsiveness in NO-GC1-KOs. In addition, conscious NO-GC2-KOs showed a higher breathing rate with a shorter duration of inspiration and expiration time, which remained faster even in the presence of bronchoconstrictors that slow down breathing. Thus, we provide evidence of two distinct NO/cGMP pathways in airways, accomplished by either NO-GC1 or NO-GC2, adjusting differentially the airway reactivity.

Mixed venous oxygen tension is a crucial prognostic factor in pulmonary hypertension: a retrospective cohort study

BackgroundThe prognostic value of mixed venous oxygen tension (PvO2) at pulmonary hypertension diagnosis treated with selective pulmonary vasodilators remains unclear. This study sought to investigate the association of PvO2 with long-term prognosis in pulmonary arterial hypertension (PAH) and medically treated chronic thromboembolic pulmonary hypertension (CTEPH) and to identify the distinct mechanisms influencing tissue hypoxia in patients with CTEPH or PAH.MethodsWe retrospectively analyzed data from 138 (age: 50.2 ± 16.6 years, 81.9% women) and 268 (age: 57.4 ± 13.1 years, 72.8% women) patients with PAH and CTEPH, respectively, diagnosed at our institution from 1983 to 2018. We analyzed the survival rates of patients with/without tissue hypoxia (PvO2 < 35 mmHg) and identified their prognostic factors based on the pulmonary hypertension risk stratification guidelines.ResultsSurvival was significantly poorer in patients with tissue hypoxia than in those without it for PAH (P = 0.001) and CTEPH (P = 0.017) treated with selective pulmonary vasodilators. In patients with PAH, PvO2 more strongly correlated with prognosis than other hemodynamic prognostic factors regardless of selective pulmonary vasodilators usage. PvO2 was the only significant prognostic factor in patients with CTEPH treated with pulmonary hypertension medication. Patients with CTEPH experiencing tissue hypoxia exhibited significantly poorer survival than those in the intervention group (P < 0.001). PvO2 more strongly correlated with the cardiac index (CI) than the alveolar-arterial oxygen gradient (A-aDO2) in PAH; whereas in CTEPH, PvO2 was more strongly correlated with A-aDO2 than with CI.ConclusionsPvO2 may represent a crucial prognostic factor for pulmonary hypertension. The prognostic impact of tissue hypoxia affects different aspects of PAH and CTEPH, thereby reflecting their distinct pathogenesis.

A retrospective review of implementation of an inhaled epoprostenol protocol in the emergency department

IntroductionInhaled epoprostenol is a selective pulmonary vasodilator that has shown a potentially broad number of applications in the management of critically ill patients. To date, the vast majority of the literature with regard to efficacy, indications for use, and adverse effects of inhaled epoprostenol is focused on use of this agent in critical care settings, with relatively little literature describing use of inhaled epoprostenol in the Emergency Department. This retrospective review sought to examine instances in which inhaled epoprostenol was administered in the Emergency Department of a tertiary-care, Level I trauma center following implementation of a clinical pathway for administration of this medication for cases of refractory hypoxemia, RV dysfunction, and refractory hypoxemia. Primary outcomes were monitoring for adverse effects (i.e. hypotension), trend in FiO2 requirement over time, and clinical indication for initiation of inhaled epoprostenol. MethodsAn automated review was performed to query cases in which inhaled epoprostenol had been initiated in the Emergency Department following adoption of the inhaled epoprostenol clinical pathway. Cases were excluded if the medication was initiated in the prehospital setting, ordered but not administered, or administered for a period of <1 h. Vital signs and co-administration of vasopressors were followed before and following epoprostenol administration to assess for change over time. Clinical indication of epoprostenol administration was assessed via manual chart review. ResultsInhaled epoprostenol was administered in 20 instances, with 15 cases ultimately meeting inclusion criteria. There were no cases of clinically significant hypotension (MAP <65) in any of the cases in which inhaled epoprostenol was administered in the Emergency Department, and mean vasopressor requirement did not increase over time. A majority of patients saw a reduction in FiO2 requirement following administration of inhaled epoprostenol. The most common indication for initiation of inhaled epoprostenol based on manual chart review was pulmonary embolism. DiscussionIn this review of cases in which inhaled epoprostenol was administered following adoption of a clinical pathway for medication administration, there were no cases of hypotension or other adverse effects that appear to be attributable to medication administration. Pulmonary embolism and refractory hypoxemia were the most common noted indications for administration of inhaled epoprostenol. Further research is warranted regarding development of clinical protocols for administration of inhaled pulmonary vasodilators in the Emergency Department setting.