Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial.

OBJECTIVE: To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN. STUDY DESIGN: Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures. RESULTS: Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related. CONCLUSIONS: IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.

Short-Term Effects of Inhaled Nitric Oxide on Right Ventricular Flow Hemodynamics by 4-Dimensional-Flow Magnetic Resonance Imaging in Children With Pulmonary Arterial Hypertension.

Background Pulmonary arterial hypertension (PAH) manifests with progressive right ventricular (RV) dysfunction, which eventually impairs the left ventricular function. We hypothesized that 4-dimensional-flow magnetic resonance imaging can detect flow hemodynamic changes associated with efficient intracardiac flow during noninvasive inhaled nitric oxide (iNO) challenge in children with PAH. Methods and Results Children with PAH (n=10) underwent 2 same-day separate iNO challenge tests using: (1) 4-dimensional-flow magnetic resonance imaging and (2) standard catheterization hemodynamics. Intracardiac flow was evaluated using the particle tracking 4-flow component analysis technique evaluating the direct flow, retained inflow, delayed ejection flow, and residual volume. Respective flow hemodynamic changes were compared with the corresponding catheterization iNO challenge results. The RV analysis revealed decreased direct flow in patients with PAH when compared with controls (P<0.001) and increase in residual volume (P<0.001). Similarly, the left ventricular analysis revealed decreased direct flow in patients with PAH when compared with controls (P=0.004) and increased proportion of the residual volume (P=0.014). There was an increase in the RV direct flow during iNO delivery (P=0.009), with parallel decrease in the residual volume (P=0.008). Conclusions Children with PAH have abnormal biventricular flow associated with impaired diastolic filling. The flow efficiency is significantly improved in the RV on iNO administration with no change in the left ventricle. The changes in the RV flow have occurred despite the minimal change in catheterization hemodynamics, suggesting that flow hemodynamic evaluation might provide more quantitative insights into vasoreactivity testing in PAH.

Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass.

OBJECTIVE: Nitric oxide (NO) plays several protective roles in ischemia/reperfusion (I/R) injury. Neonates undergoing the Norwood procedure are subject to develop I/R injury due to the immaturity of their organs and the potential need to interrupt or decrease systemic flow during surgery. We hypothesized that NO administration during cardiopulmonary bypass (CPB) ameliorates the I/R and could help the postoperative recovery after the Norwood procedure. METHODS: Twenty-four neonates who underwent a Norwood procedure were enrolled in a prospective randomized blinded controlled trial to receive NO (12 patients) or placebo (12 patients) into the oxygenator of the CPB circuit during the Norwood procedure. Markers of I/R injury were collected at baseline (T0), after weaning from CPB before modified ultrafiltration (T1), after modified ultrafiltration (T2), and at 12 hours (T3) and 24 hours (T4) after surgery, and they were compared between both groups, as well as other postoperative clinical variables. RESULTS: There was no difference in age, weight, anatomical diagnosis, CPB, and aortic cross-clamp time between both groups. Troponin levels were lower in the study group at T1 (0.62 ± 58 ng/mL vs 0.87 ± 0.58 ng/mL, P = .31) and became significantly lower at T2 (0.36 ± 0.32 ng/mL vs 0.97 ± 0.48 ng/mL, P = .009).There were no significant differences between both groups for all other markers. Despite a lower troponin level, there was no difference in inotropic scores or ventricular function between both groups. Time to start diuresis, time to sternal closure and extubation, and intensive care unit and hospital stay were not different between both groups. CONCLUSION: Systemic administration of NO during the Norwood procedure has myocardial protective effects (lower Troponin levels) but we observed no effect on postoperative recovery. Larger sample size may be needed to show clinical differences.

Combination of PGE1 and Pulmonary Vasodilator Therapy in Managing a Challenging Case of Severe PAH Secondary to CDH.

Congenital diaphragmatic hernia (CDH) is a rare disease, which affects 1 in 2,500 newborns. Congenital diaphragmatic hernia can interfere with the normal development of the pulmonary parenchyma and vascular bed, and in severe cases, it can lead to the development of severe pulmonary arterial hypertension (PAH) and right ventricular failure. We present a neonate with CDH who developed severe PAH and right ventricular dysfunction and was managed with a unique strategy combining venoarterial extracorporeal membrane oxygenation, prostaglandin E1, and a variety of PAH therapies.

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

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

Protocol of a randomised controlled trial in cardiac surgical patients with endothelial dysfunction aimed to prevent postoperative acute kidney injury by administering nitric oxide gas.

INTRODUCTION: Postoperative acute kidney injury (AKI) is a common complication in cardiac surgery. Levels of intravascular haemolysis are strongly associated with postoperative AKI and with prolonged (>90 min) use of cardiopulmonary bypass (CPB). Ferrous plasma haemoglobin released into the circulation acts as a scavenger of nitric oxide (NO) produced by endothelial cells. Consequently, the vascular bioavailability of NO is reduced, leading to vasoconstriction and impaired renal function. In patients with cardiovascular risk factors, the endothelium is dysfunctional and cannot replenish the NO deficit. A previous clinical study in young cardiac surgical patients with rheumatic fever, without evidence of endothelial dysfunction, showed that supplementation of NO gas decreases AKI by converting ferrous plasma haemoglobin to ferric methaemoglobin, thus preserving vascular NO. In this current trial, we hypothesised that 24 hours administration of NO gas will reduce AKI following CPB in patients with endothelial dysfunction. METHODS: This is a single-centre, randomised (1:1) controlled, parallel-arm superiority trial that includes patients with endothelial dysfunction, stable kidney function and who are undergoing cardiac surgery procedures with an expected CPB duration >90 min. After randomisation, 80 parts per million (ppm) NO (intervention group) or 80 ppm nitrogen (N2, control group) are added to the gas mixture. Test gases (N2 or NO) are delivered during CPB and for 24 hours after surgery. The primary study outcome is the occurrence of AKI among study groups. Key secondary outcomes include AKI severity, occurrence of renal replacement therapy, major adverse kidney events at 6 weeks after surgery and mortality. We are recruiting 250 patients, allowing detection of a 35% AKI relative risk reduction, assuming a two-sided error of 0.05. ETHICS AND DISSEMINATION: The Partners Human Research Committee approved this trial. Recruitment began in February 2017. Dissemination plans include presentations at scientific conferences, scientific publications and advertising flyers and posters at Massachusetts General Hospital. TRIAL REGISTRATION NUMBER: NCT02836899.

Ventricular Septal Defect in a 66-Year-Old Man.

A 66-year-old man presented with a moderate-sized ventricular septal defect and severe pulmonary hypertension that was responsive to vasodilator therapy. His electrocardiogram demonstrated biatrial enlargement and biventricular hypertrophy. Presentation at this age is unusual for this type of shunt.

Nitric Oxide in Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To investigate the efficacy and safety of perioperative administration of nitric oxide in cardiac surgery. DESIGN: Meta-analysis of randomized controlled trials (RCTs). PARTICIPANTS: Cardiac surgery patients. INTERVENTIONS: A search of Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and MEDLINE for RCTs that compared nitric oxide with placebo or other comparators. MEASUREMENTS AND MAIN RESULTS: The primary outcome was intensive care unit (ICU) stay, and secondary outcomes were mortality, duration of mechanical ventilation, and reduction of mean pulmonary artery pressure. The study included 18 RCTs comprising 958 patients. The authors calculated the pooled odds ratio (OR) and the mean difference (MD) with random-effects model. Quantitative synthesis of data demonstrated a clinically negligible reduction in the length of ICU stay (MD -0.38 days, confidence interval CI [-0.65 to -0.11]; p = 0.005) and mechanical ventilation duration (MD -4.81 hours, CI [-7.79 to -1.83]; p = 0.002) compared with all control interventions with no benefit on mortality. CONCLUSIONS: Perioperative delivery of inhaled nitric oxide resulted to be of no or minimal benefit in patients with pulmonary hypertension undergoing cardiac surgery. Large, randomized trials are needed to further assess its effect on major clinical outcomes and its cost-effectiveness.

Enhanced tumor therapy via drug co-delivery and in situ vascular-promoting strategy.

Conventional tumor starving therapy by reducing its vessel density may be effective at early treatment but potentially contributes to tumor hypoxia, drug resistance and metastasis. A new strategy through enhancing tumor angiogenesis in combination with effective chemotherapeutic drugs, has shown successful tumor growth and spread inhibition. To achieve in situ release of angiogenic and antitumor drugs in tumor, we designed a precise ratiometric polymeric hybrid micelle system for co-delivering nitric oxide and paclitaxel. The hybrid micelles could accumulate in tumor via the long blood circulation and enhanced permeability and retention (EPR) effect, promote the drug accumulation and penetration in tumor by in situ increased vascular permeability, blood perfusion and vessel density, achieve the synergistic antitumor effect of nitric oxide and paclitaxel through modified tumor microenvironment, overcome multidrug resistance and inhibit metastasis. This study presents a combinational therapy against tumor progression and spread, which shows great potential in cancer therapy of the future.

Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn.

Objective To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Design Randomized, open label pilot study. Setting Multicenter; level 3 and level 4 neonatal intensive care units. Patients Six infants ≥34 weeks' gestational age and <10 days of life with persistent hypoxemia receiving inhaled nitric oxide. Intervention Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. Measurements and Main Results The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. Conclusion The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure.

A prospective, randomized study of inhaled prostacyclin versus nitric oxide in patients with residual pulmonary hypertension after pulmonary endarterectomy.

OBJECTIVES: Pulmonary endarterectomy (PEA) is an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but postoperative residual hypertension leads to in-hospital mortality. Inhaled epoprostenol sodium (PGI2) and NO are administered for pulmonary hypertension after cardiothoracic surgery. This prospective study provides the first comparative evaluation of the effects of inhaled PGI2 and NO on pulmonary hemodynamics, systemic hemodynamics, and gas exchange in patients developing residual pulmonary hypertension after PEA. METHODS: Thirteen patients were randomized to receive either NO (n = 6) or PGI2 (n = 7) inhalation when pulmonary hypertension persisted after weaning from cardiopulmonary bypass. Hemodynamic and respiratory variables were measured before inhalation of the agent (T0); 30 min (T1), 3 h (T2), and 6 h after inhalation (T3); and the next morning (T4). The NO dose was started at 20 ppm and gradually tapered until extubation, and PGI2 was administered at a dose of 10 ng kg-1 min-1. RESULTS: In both groups, mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) significantly decreased over time until T4 (mean PAP: p < 0.0001; PVR: p = 0.003), while mean systemic arterial blood pressure significantly increased (p = 0.028). There were no significant between-group differences in patient characteristics, cardiac index, left atrial pressure, or ratio of arterial oxygen tension to fraction of inspired oxygen. There were no in-hospital deaths. CONCLUSIONS: Both inhaled PGI2 and NO significantly reduced PAP and PVR without adverse effects on systemic hemodynamics in patients who developed residual pulmonary hypertension after PEA. Inhaled PGI2 can be offered as alternative treatment option for residual pulmonary hypertension.

Acute Vasodilator Response in Pediatric Pulmonary Arterial Hypertension: Current Clinical Practice From the TOPP Registry.

BACKGROUND: In pulmonary arterial hypertension (PAH), acute vasodilator response testing (AVT) is considered important to identify adult patients with favorable prognosis using calcium-channel blocker (CCB) therapy. However, in pediatric PAH, criteria used to identify acute responders and CCB use are insufficiently studied. OBJECTIVES: This study sought to describe current clinical practice of AVT and subsequent treatment decisions in pediatric PAH. METHODS: From January 2008 to May 2013, 529 consecutive children with confirmed pulmonary hypertension were enrolled in an international registry. We analyzed those children with evaluable AVT. RESULTS: Of 382 children with evaluable AVT, 212 had idiopathic/familial PAH (IPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide; other agents were used in the remaining patients. In IPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL (Registry-to-Evaluate-Early-And-Long-term PAH disease management)-pediatric criteria, and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%), and 7 (7%) respectively. Correlation between AVT responder status as judged by the treating physician and by published response criteria was poor. Moreover, of the IPAH/FPAH patients judged by the treating physician as acute responders, only 23% were treated with CCB without additional PAH-targeted therapy. The Sitbon criteria selected patients with better prognosis who had excellent outcome when treated with CCB. CONCLUSIONS: The current practice of identifying responders to AVT and subsequent treatment with CCB therapy demonstrated large discrepancies with current international guidelines. Also, in pediatric IPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy.

Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study.

PURPOSE: Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS). METHODS: To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N = 50) gas or inhaled nitrogen placebo (N = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO2/FiO2 ≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy. RESULTS: The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups [23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54-1.16; p = 0.23]. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 [7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06-0.68; p = 0.009]. CONCLUSIONS: iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia. CLINICAL TRIAL REGISTRATION: NCT00748423.

Nitric oxide inhalation for myocardial infarction patients.

Nitric oxide inhalation in myocardial infarction patients sends mixed messages, but may offer some benefit.

Effect of acute arteriolar vasodilation on capacitance and resistance in pulmonary arterial hypertension.

BACKGROUND: Pulmonary vascular capacitance (PVC) is reduced in pulmonary arterial hypertension (PAH). In normal lung, PVC is largely a function of vascular compliance. In PAH, increased pulmonary vascular resistance (PVR) arises from the arterioles. PVR and PVC share pressure and volume variables. The dependency between the two qualities of the vascular bed is unclear in a state of intense vasoconstriction. METHODS: We compared PVC and PVR before and during nitric oxide (NO) inhalation during right-sided heart catheterization in eight NO-responsive patients with PAH. NO only directly affects tone in parenchymal vessels. RESULTS: During NO inhalation, pulmonary arterial systolic pressure decreased, 80 ± 20 SD to 48 ± 20 mm Hg, and stroke volume increased, 62 ± 19 mL to 86 ± 24 mL (P < .01). PVR dropped from 10 ± 4.4 Wood units to 4.7 ± 2.2 Wood units (P < .012), and PVC increased from 1.4 ± 1.1 mL/mm Hg to 3.2 ± 1.8 mL/mm Hg (P < .018). The magnitude of PVR drop was 57% ± 6% and the decrease in 1/PVC was 54% ± 14% (P = not significant). CONCLUSIONS: In vasoresponsive PAH, PVC is a function of the pressure response of the vasoconstricted arterioles to stroke volume. Immediately upon vasodilation, the capacitance increases markedly. The compliance vessels are, thus, the same as the resistance vessels. The immediate reduction in pulmonary arterial pressure during NO inhalation suggests that large vessel remodeling is not a major contributor to systolic pressure in these patients.

[Clinical aspects of vaso-and cardioprotection in patients with primary and recurrent myocardial infarction].

The paper is devoted to characteristics of vascular and cardiac remodeling in patients with primary and recurrent myocardial infarction (MI). Data on multifocal atheroslerotic involvement of vessels in these patients associated with development of multivascular involvement of coronary arteries are presented. Emphasis is made on remodeling of vessels and the heart, parameters of vasodilation. We have elucidated frequency of vascular vasoconstrictory reactions in acute stage of MI and relationship between vascular and myocardial remodeling. Special consideration is given to possibility of correction of vascular vasoconstrictory reaction with indapamide. We have corroborated its administration starting from first days of treatment and demonstrated its effect during use for 3 months. We have established possibility of normalization of endothelium dependent vasodilation in most patients with primary MI. Expedience of the use of indapamide for prevention of development of chronic heart failure is stressed.

Our paper 20 years later: Inhaled nitric oxide for the acute respiratory distress syndrome--discovery, current understanding, and focussed targets of future applications.

INTRODUCTION: More than 20 years have passed since we reported our results of treating patients with the acute respiratory distress syndrome (ARDS) with inhaled nitric oxide (iNO). The main finding was that iNO alleviated pulmonary hypertension (PH) by selective vasodilation of pulmonary vessels in ventilated lung areas. This, in turn, improved arterial oxygenation. METHODS: We now set out to review the time span between the discovery of NO in 1987 and today in order to identify and describe interesting areas of research and clinical practice surrounding the application of iNO. MAJOR FINDINGS: Enhancement of ventilation-perfusion matching and alleviation of PH in ARDS, treatment of PH of the newborn, and treatment of perioperative PH in congenital heart disease serve as just a few exciting examples for the successful use of iNO. Breathing NO prevents PH induced by stored blood transfusions or sickle cell disease. Exploiting the anti-inflammatory properties of NO helps to treat malaria. DISCUSSION: Regarding the use of iNO in ARDS, there remains the unresolved question of whether important outcome parameters can be positively influenced. At first glance, several randomized controlled trials and meta-analyses seem to send the clear message: "There is none!" Careful analyses, however, leave sufficient room for doubt that the ideal study to produce the unequivocal proof for the inability of iNO to positively impact on important outcome parameters has, as yet, not been conducted. CONCLUSION: In summary, the discovery of and research on the many positive effects of iNO has improved care of critically ill patients worldwide. It is a noble effort to continue on this path.