Project description:AimsThe 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 resultsThis 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.ConclusionsPatients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.
Project description:BackgroundRight 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.MethodsIn 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.ResultsOf 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.ConclusionsAmong 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.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT03081052.
Project description:AimsRight heart catheterization (RHC) is indicated in all candidates for heart transplantation (HT). An acute vasodilator challenge is recommended for those with pulmonary hypertension (PH) to assess its reversibility. The effects of inhaled nitric oxide (iNO) on pulmonary and systemic haemodynamics have been reported only in small series. Our purpose was to describe the response to iNO in a larger population and its potential clinical implications.Methods and resultsFrom 210 RHC procedures performed between 2010 and 2019, vasodilator challenge with iNO was used in 108 patients, of which 66 had advanced heart failure undergoing assessment for HT (55±11 years old; 74.2% male gender; 43.9% ischaemic cardiomyopathy; left ventricular ejection fraction 28.4 ± 11,4%; and peak VO2 12.1 ± 3.0 mL/kg/min). iNO was administered through a tight-fitting facial mask regardless of baseline pulmonary pressures. Clinical endpoints (all-cause mortality and acute right heart failure) were assessed according to baseline haemodynamic findings over the available follow-up period. There were no side effects from iNO administration. Typical response consisted of a reduction in pulmonary vascular resistance, consequent to an increase in left ventricular filling pressures, no significant change in mean pulmonary artery pressure (resulting in a lower mean transpulmonary gradient) and a mild increase in cardiac ouput. Pulmonary arterial compliance increased significantly, whereas systemic vascular resistance was only mildly affected. In five cases (7.6%), pulmonary vascular resistance increased paradoxically. All-cause mortality and post-HT right heart failure events were overall low and similar in patients without PH or reversible PH.ConclusionsVasodilator challenge with iNO is safe in advanced heart failure patients undergoing RHC prior to HT listing. It produces a reasonably predictable haemodynamic response, which occurs predominantly at the pulmonary circulation level. Clinical implications of iNO-induced reversibility may be relevant, but further systematic validation is warranted in larger cohorts.
Project description:Combination therapy with venoarterial extracorporeal membrane oxygenation (VA-ECMO) and Impella (ECPELLA) has been known to be a favorable strategy of mechanical circulation support for patients with fatal cardiogenic shock. However, the practical strategy for weaning ECPELLA in patients with right ventricular (RV) dysfunction remains unclear. We describe a case of a 63-year-old male with fulminant myocarditis presenting with cardiogenic shock who required ECPELLA to improve hemodynamics. Because of persistent severe RV dysfunction despite the introduction of intravenous dobutamine and milrinone, VA-ECMO could not be weaned. Inhaled nitric oxide (iNO) was introduced at 20 ppm to reduce RV afterload, resulting in increased cardiac output (from 1.6 to 5.5 L/min) and ameliorated RV performance (the pulmonary artery pulsatility index was from 0.47 to 1.11). Subsequently, VA-ECMO could be weaned. iNO, a selective pulmonary vasodilator, reduces pulmonary vascular resistance, resulting in reduced RV afterload. This is the first case of iNO usage for the management of cardiogenic shock supported by ECPELLA. iNO could be a favorable strategy in ECPELLA patients with refractory RV dysfunction for weaning VA-ECMO through bridging to recovery.Learning objectiveThe practical strategy for weaning venoarterial extracorporeal membrane oxygenation and Impella (ECPELLA) in patients with concomitant right ventricular dysfunction remains unclear. Inhaled nitric oxygen is a novel weaning strategy for patients with biventricular dysfunction supported by ECPELLA. If the response of inhaled nitric oxygen was insufficient under ECPELLA support, implantable ventricular assist devices or transplantation should be considered.
Project description:ObjectivesTo characterize contemporary use of inhaled nitric oxide in pediatric acute respiratory failure and to assess relationships between clinical variables and outcomes. We sought to study the relationship of inhaled nitric oxide response to patient characteristics including right ventricular dysfunction and clinician responsiveness to improved oxygenation. We hypothesize that prompt clinician responsiveness to minimize hyperoxia would be associated with improved outcomes.DesignAn observational cohort study.SettingEight sites of the Collaborative Pediatric Critical Care Research Network.PatientsOne hundred fifty-one patients who received inhaled nitric oxide for a primary respiratory indication.Measurements and main resultsClinical data were abstracted from the medical record beginning at inhaled nitric oxide initiation and continuing until the earliest of 28 days, ICU discharge, or death. Ventilator-free days, oxygenation index, and Functional Status Scale were calculated. Echocardiographic reports were abstracted assessing for pulmonary hypertension, right ventricular dysfunction, and other cardiovascular parameters. Clinician responsiveness to improved oxygenation was determined. One hundred thirty patients (86%) who received inhaled nitric oxide had improved oxygenation by 24 hours. PICU mortality was 29.8%, while a new morbidity was identified in 19.8% of survivors. Among patients who had echocardiograms, 27.9% had evidence of pulmonary hypertension, 23.1% had right ventricular systolic dysfunction, and 22.1% had an atrial communication. Moderate or severe right ventricular dysfunction was associated with higher mortality. Clinicians responded to an improvement in oxygenation by decreasing FIO2 to less than 0.6 within 24 hours in 71% of patients. Timely clinician responsiveness to improved oxygenation with inhaled nitric oxide was associated with more ventilator-free days but not less cardiac arrests, mortality, or additional morbidity.ConclusionsClinician responsiveness to improved oxygenation was associated with less ventilator days. Algorithms to standardize ventilator management may improve signal to noise ratios in future trials enabling better assessment of the effect of inhaled nitric oxide on patient outcomes. Additionally, confining studies to more selective patient populations such as those with right ventricular dysfunction may be required.
Project description:Ischemic stroke is a major global health issue and characterized by acute vascular dysfunction and subsequent neuroinflammation. However, the relationship between these processes remains elusive. In the current study, we investigated whether alleviating vascular dysfunction by restoring vascular nitric oxide (NO) reduces post-stroke inflammation. Mice were subjected to experimental stroke and received inhaled NO (iNO; 50 ppm) after reperfusion. iNO normalized vascular cyclic guanosine monophosphate (cGMP) levels, reduced the elevated expression of intercellular adhesion molecule-1 (ICAM-1), and returned leukocyte adhesion to baseline levels. Reduction of vascular pathology significantly reduced the inflammatory cytokines interleukin-1β (Il-1β), interleukin-6 (Il-6), and tumor necrosis factor-α (TNF-α), within the brain parenchyma. These findings suggest that vascular dysfunction is responsible for leukocyte adhesion and that these processes drive parenchymal inflammation. Reversing vascular dysfunction may therefore emerge as a novel approach to diminish neuroinflammation after ischemic stroke and possibly other ischemic disorders.
Project description:ObjectiveTo describe temporal changes in inhaled nitric oxide (iNO) use in English neonatal units between 2010 and 2015.DesignRetrospective analysis using data extracted from the National Neonatal Research Database.SettingAll National Health Service neonatal units in England.PatientsInfants of all gestational ages born 2010-2015 admitted to a neonatal unit and received intensive care.Main outcome measuresProportion of infants who received iNO; age at initiation and duration of iNO use.Results4.9% (6346/129 883) of infants received iNO; 31% (1959/6346) were born <29 weeks, 18% (1152/6346) 29-33 weeks and 51% (3235/6346)>34 weeks of gestation. Between epoch 1 (2010-2011) and epoch 3 (2014-2015), there was (1) an increase in the proportion of infants receiving iNO: <29 weeks (4.9% vs 15.9%); 29-33 weeks (1.1% vs 4.8%); >34 weeks (4.5% vs 5.0%), (2) increase in postnatal age at iNO initiation: <29 weeks 10 days vs 18 days; 29-33 weeks 2 days vs 10 days, (iii) reduction in iNO duration: <29 weeks (3 days vs 2 days); 29-33 weeks (2 days vs 1 day).ConclusionsBetween 2010 and 2015, there was an increase in the use of iNO among infants admitted to English neonatal units. This was most notable among the most premature infants with an almost fourfold increase. Given the cost of iNO therapy, limited evidence of efficacy in preterm infants and potential for harm, we suggest that exposure to iNO should be limited, ideally to infants included in research studies (either observational or randomised placebo-controlled trial) or within a protocolised pathway. Development of consensus guidelines may also help standardise practice.
Project description:BackgroundRecently, mechanical support obtained with the combination of venoarterial extracorporeal membrane oxygenation (VA-ECMO) and an Impella device, together referred to as ECPELLA, has been shown to be effective for acute myocardial infarction with cardiogenic shock. However, methods for withdrawing VA-ECMO in acute myocardial infarction cases complicated by right ventricular dysfunction are yet to be established. Here, we report the effective use of inhaled nitric oxide during the weaning of VA-ECMO from the ECPELLA management of a patient with acute myocardial infarction with cardiogenic shock.Case summaryAn 81-year-old man with an acute extensive anterior wall myocardial infarction with cardiogenic shock was supported with ECPELLA to improve his haemodynamics. During ECPELLA, the Impella device could not maintain sufficient flow. Echocardiography revealed a small left ventricle and an enlarged right ventricle, indicating acute right heart failure. Inhaled nitric oxide was initiated to reduce right ventricle afterload, which decreased pulmonary artery pressure from 34/20 to 27/13 mmHg, improved right and left ventricle sizes, and stabilized the Impella support. Afterward, VA-ECMO could be withdrawn because the Impella alone was sufficient for haemodynamic support.DiscussionInhaled nitric oxide improved right ventricle performance in a patient with severe myocardial infarction with right heart failure supported by ECPELLA. Thus, we suggest that inhaled nitric oxide facilitates the weaning of VA-ECMO from patients with refractory right ventricular dysfunction who are supported by ECPELLA.