Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH)

INTRODUCTION: Although surgery is the treatment of choice for CTEPH, it is not appropriate for patients with surgically inaccessible distal disease. These patients are traditionally managed supportively, but may benefit from newer, more specific vasoactive therapies. This study examines the acute haemodynamic responses to inhaled nitric oxide (iNO) and intravenous sildenafil in this patient population. METHODS: Nine patients with de novo distal CTEPH and nine with persistent pulmonary hypertension post-pulmonary endarterectomy (PEA) were enrolled. At right heart catheterisation, following baseline haemodynamic measurements, iNO was administered at 20 ppm for 10 min. Following repeat measurements, iNO was discontinued with a subsequent washout period of 10 min. Sildenafil was then administered intravenously at two doses, to achieve plasma levels equivalent to 25 mg and 50 mg orally, with further measurements obtained at the end of each infusion. RESULTS: Significant reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were demonstrated following both iNO (-4.3 mm Hg or -10.3% p=0.001 and -101 dyn/s/cm(5) or -15.6% p<0.001) and sildenafil (-7.4 mm Hg or -16.9% p<0.001 and -188.8 dyn/s/cm(5) or -25.1% p<0.001). Individual mPAP and cardiac output (CO) responses to iNO and sildenafil correlated well, but haemodynamic changes following sildenafil were consistently more marked. There was, however, no difference in effect between the two doses of sildenafil. Although sildenafil caused significant reductions in systemic vascular resistance, the net haemodynamic effect of sildenafil remained pulmonary selective. Subgroup analysis suggested that post-PEA patients were more responsive to both iNO and sildenafil than de novo patients. DISCUSSION: Although all but one patient failed to fulfil the formal haemodynamic response criteria typically used in idiopathic pulmonary arterial hypertension (IPAH), subjects displayed significant acute responses to both iNO and sildenafil suggesting that increased vascular tone forms an important component of distal CTEPH. It is possible that these acute haemodynamic responses may translate to improved clinical outcomes, and thus further long term trials of sildenafil in distal CTEPH are warranted.     

应用一氧化氮吸入治疗新生儿持续性肺动脉高压的临床效果分析

目的对一氧化氮吸入(Inhaled nitric oxide,iNO)治疗新生儿持续性肺动脉高压(Persistent pulmonary hypertension of newborn,PPHN)的临床效果进行分析。方法 2016年1月至2019年6月我院新生儿病房收治的重度PPHN患儿共80例,分为iNO组(iNO+机械通气)40例和常规组(单独应用机械通气)40例,比较两组患儿住院时间、机械通气时间、氧疗时间、肺动脉压力、血气离子分析及呼吸功能。结果 iNO组患儿使用机械通气时间、氧疗时间均小于常规组,肺动脉压力低于常规组,差异均有统计学意义(P<0.05)。iNO组和常规组平均气道压(Mean airway pressure,MAP)、氧合指数(Oxygenation index,OI)及pH值组间、时间及组间×时间交互作用差异有统计学意义(P<0.05)。结论对新生儿持续性肺动脉高压患儿使用一氧化氮吸入联合机械通气治疗可以明显改善患儿呼吸功能,从而减少机械通气时间、氧疗时间和住院时间。     

Combination therapy with inhaled nitric oxide and intravenous dobutamine during pulmonary hypertension in the rabbit

Combination therapy with an intravenous inovasodilator and inhaled nitric oxide (NO) may be appropriate in patients with pulmonary hypertension and associated right ventricular failure. We examined whether dobutamine and inhaled NO would have additive pulmonary vasodilator effects in experimental pulmonary hypertension. Pulmonary hypertension was produced in anesthetized, mechanically ventilated rabbits by infusion of U46619, a thromboxane analogue. Dobutamine was administered in increasing doses (2.5-20 microg/kg/min) with and without inhaled NO (40 ppm). Dobutamine produced dose-dependent decreases in pulmonary vascular resistance (PVR) and mean arterial pressure (MAP) and increases in cardiac output (CO). Inhaled NO alone decreased pulmonary artery pressure (PAP) and PVR with no effect on MAP or CO. The effects of dobutamine and inhaled NO were additive, so that at each dose of dobutamine, inhaled NO decreased PAP and PVR with no effect on systemic hemodynamics. This study suggests that the combination of dobutamine and inhaled NO should produce additive pulmonary vasodilation in patients with pulmonary hypertension and associated right ventricular dysfunction.     

Cost implications of using inhaled nitric oxide compared with epoprostenol for pulmonary hypertension.

OBJECTIVE: To compare the cost of using intravenous epoprostenol with that of inhaled nitric oxide (NO) for treating episodes of pulmonary hypertension in children with congenital heart disease. DESIGN: An analysis of the cost of epoprostenol and NO use over the previous 18 months was performed. Three 6-month periods were identified, two in which epoprostenol was used and the third in which inhaled NO was introduced for the treatment of pulmonary hypertension. SETTING: A 10-bed pediatric cardiac intensive care unit, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, England. SUBJECTS: Children with congenital heart disease and persistently elevated pulmonary artery pressure following cardiac surgery. MAIN OUTCOME MEASURES: The total duration of use of epoprostenol and inhaled NO was documented. The costs per hour for epoprostenol and inhaled NO were calculated and the annual cost of each agent was estimated. RESULTS: In the two 6-month periods prior to the introduction of inhaled NO, epoprostenol was used on 14 occasions (5 in the first period, 3 in the second). In the last 6-month period, nine children required pulmonary vasodilator therapy on 14 occasions. All nine children were treated successfully with inhaled NO; none were given or needed epoprostenol, as NO always was effective in providing pulmonary vasodilatation. For resistant pulmonary hypertension, increasing the concentration of NO would have been the next therapeutic option. The cost for the two 6-month periods using epoprostenol was $19,483.48 for the drug and $283.25 for equipment costs (total cost $19,766.73). There was no expenditure on epoprostenol in the final 6-month period. The cost of NO was $465. However, the total expenditure, including the delivery and monitoring system, was $4,722.85. CONCLUSIONS: Using inhaled NO in our pediatric cardiac intensive care unit abolished the use of epoprostenol during the reported monitoring period. The cost savings were significant, amounting to 12% of the annual drug budget for the unit. The cost of setting up the inhaled NO delivery system is recouped rapidly. The ease of delivery and measurement of inhaled NO also may have contributed to its increased clinical use.     

The toxicology of inhaled nitric oxide.

Inhaled nitric oxide is a targeted pulmonary vasodilator that improves clinical outcomes for newborn patients with persistent pulmonary hypertension of the newborn, and may be effective in treating some premature patients with acute respiratory distress syndrome or lung disease of prematurity. Nitric oxide is now recognized as playing an important role in the regulation of diverse physiological processes. However, the pharmacological properties of inhaled nitric oxide are not easy to separate from its toxicological effects. For example, the intended effect of inhaled nitric oxide, vasodilation in the lung, is mediated, in part, by increased cellular cyclic GMP (cGMP). However, increased cGMP can also interfere with normal cellular proliferation. Nitric oxide has also been shown to cause DNA strand breaks and/or base alterations that are potentially mutagenic. Inhaled nitric oxide can rapidly react with oxygen in the lung to form nitrogen dioxide, which is a potent pulmonary irritant. Nitric oxide also reacts with superoxide anion to form peroxynitrite, a cytotoxic oxidant that can interfere with surfactant functioning. The overall effect of inhaled nitric oxide in potentiating or attenuating inflammation and oxidative damage in diseased lung is dependent on the dose administered. Furthermore, despite rapid inactivation by circulating hemoglobin, inhaled nitric oxide exerts effects outside the lung, including blocking platelet aggregation, causing methemoglobinemia, and possibly inducing extrapulmonary vasodilation. The toxicology of inhaled nitric oxide is not completely understood and must be considered in the design of protocols for its safe and effective clinical use.     

NO吸入治疗室间隔缺损术后肺动脉高压疗效观察

目的评估吸入一氧化氮(NO)治疗室间隔缺损患者术后重度肺动脉高压的疗效。方法回顾性分析2008年1月~2010年10月我院收治的32例室间隔缺损合并重度肺动脉高压患者术后吸入NO前后的心率、平均动脉压、中心静脉压、动态肺顺应性及氧合指数的变化。结果 32例患者在其他治疗不变的前提下,经过吸入NO治疗后,患者心率、血压无明显改变,动态肺顺应性比治疗前明显改善(0.30±0.03vs0.38±0.09,P<0.05),氧合指数比治疗前明显增高(296.3±55.64vs378.5±61.32,P<0.05),差异有统计学意义。结论吸入NO对治疗室间隔缺损术后肺动脉高压具有良好的临床效果。     

Consensus on surfactant and inhaled nitric oxide for ARDS.

Adult respiratory distress syndrome (ARDS) remains a major problem in intensive care medicine. While the triggers are not well understood, the process often involves generalized neutrophil activation and sequestration in the lung which initiate inflammatory cascades. These effects can be localized to the pulmonary tissues as well as diffusely throughout the body. Should the latter occur, the patient presents with multiple organ failure (MOF). Attempts to interfere with this series of events have included replacement therapy for surfactant and its components because of observations that the natural surfactant mechanisms are impaired or damaged. The effectiveness of replacement therapy has been tested in various protocols involving synthetic composites and animal (bovine) surfactants. While major differences in protocol design have led to conflicting results, there appears to be evidence that installation of bovine surfactant can reduce mortality in ARDS. A major limitation in adult therapeutics utilizing surfactant is the method of delivery; direct instillation utilizes large quantities, thus limiting its availability. Aerosolized therapy may have promise if smaller amounts delivered by this modality are more effective. Inhaled nitric oxide may also have therapeutic potential in ARDS. By improving ventilation perfusion mismatch, ventilatory requirements can be reduced.     

Response to inhaled nitric oxide in premature and term neonates

Inhaled nitric oxide (iNO) has emerged as a promising therapeutic agent in the treatment of persistent pulmonary hypertension of the newborn. Several theories exist regarding causes of both response and nonresponse to iNO. Clinical trials differentiate disease entities (primary vs secondary persistent pulmonary hypertension associated with meconium aspiration syndrome, pneumonia or congenital diaphragmatic hernia) and their specific response rates. iNO combined with high-frequency ventilation appears to be superior to inhalation of nitric oxide (NO) during conventional ventilation. Little is known regarding the role of the degree of lung expansion and its modification -- no matter what mode of ventilation is applied. Gestational age plays an important role in relation to the potential adverse effects of NO. Of particular concern in the premature neonate is the effect of NO on bleeding time and the inhibition of platelet aggregation. Those potentially hazardous effects need to be carefully weighed against early intervention with iNO at a comparably low oxygenation index in order to prevent the vicious cycle of hypoxaemia and subsequent increased right-to-left shunting. Further studies are required to determine the optimal timing, mode of delivery and mode of ventilation used with iNO therapy in order to optimise the response of premature and term neonates.     

吸入一氧化氮联合高频振荡通气治疗新生儿持续肺动脉高压的临床研究

目的探讨吸入一氧化氮联合高频振荡通气治疗新生儿持续肺动脉高压的临床效果。方法收集2010年6月-2013年6月佛山市南海区第六人民医院、佛山市妇幼保健院、广东省妇幼保健院新生儿重症监护室新生儿持续肺动脉高压60例。根据治疗方法的不同分为治疗组与对照组各30例,两组常规给予高频振荡通气治疗,在此基础上治疗组加用吸入一氧化氮辅助治疗。结果治疗组与对照组的有效率分别为83．3％和63．3％,两组对比差异明显（P〈0．05）。两组机械通气前动脉血动脉血氧分压（PaO2）、动脉血二氧化碳分压（PaCO2）和氧合指数（OI）值对比无明显差异,机械通气后36h血PaO2和PaCO2值明显上升,而OI值明显下降,组间对比也有明显差异（P〈0．05）。两组通气前动脉肺动脉收缩（SPAP）与体体循环收缩压（SBP）值对比差异无统计学意义,通气后SPAP值明显下降,SBP值明显上升,同时组间对比差异明显（P〈0．05）。通气后治疗组肺炎、低血压、心力衰竭、败血症等总体并发症发生率明显少于对照组（P〈0．05）。结论吸入一氧化氮联合高频振荡通气治疗新生儿持续肺动脉高压安全有效,改善血气与血压指标,值得推广应用。     

重新评价吸入一氧化氮在急性肺损伤中的作用

Inhaled nitric oxide (iNO) has now been used clinically since 1991, or twelve years. The acute aims of therapy have mainly been improvement of oxygenation and reduction of lung vasoconstriction. This is true also for the use in ALl (acute lung injury) of various degrees of severity including ARDS (acute respiratorydistress syndrome).     

Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.     

Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.     

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes.

Exposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic guanosine-3',-5'-monophosphate (cyclic GMP). We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3mg/h for 5 days). Myocyte function was determined at baseline, after C-type natriuretic peptide (CNP, 10(-8) and 10(-7)M) or brain natriuretic peptide (BNP, 10(-8) and 10(-7)M) or S-nitroso-N-acetyl-penicilliamine (SNAP, a NO donor, 10(-6) and 10(-5)M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10(-6)M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10(-8)M (5.14+/-0.5%) and 10(-7)M (4.4+/-0.7%) significantly reduced percentage shortening from baseline (6.1+/-1.6%). KT5823 restored percentage shortening to 4.9+/-0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.     

一氧化氮与一氧化氮合成酶在妊高征疾病过程中的变化及其意义

目的:探讨一氧化氮(NO)和一氧化氮合成酶(NOS)在妊高征发病过程中的致病机理及其临床意义。方法:用分光光度计对正常妊娠孕妇34例(正常妊娠组)和妊高征孕妇39例(妊高征组)的血浆 NO和脐静脉血管内皮细胞 NOS 活性进行测定比较。结果:与正常妊娠组相比,妊高征组产前 NO 活性明显低于对照组(P<0.01),重度妊高征的降低尤其显著,但产后各组无显著差异;妊高征组脐血 NO 水平和跻静脉血管内皮细胞 NOS 活性明显低于正常组;正常妊娠组脐血 NO 水平比其外周血高;妊高征患者外周血 NO 水平与平均动脉压(MAP)呈显著负相关。讨论:NO 的合成、释放减少及 NOS 活性降低在妊高征的病理生理过程中起着重要作用。     

Targeted diazeniumdiolates: localized nitric oxide release from glioma-specific peptides and proteins

Nitric oxide (NO) is a small yet important biological messenger, which at sufficient concentrations has been shown to induce apoptosis as well as increase radiosensitization in tumor cells. However, the short half-life of NO gas itself has limited its utility as a therapeutic agent. The objective of this study was the development of targeted NO donors and we illustrate their utility as a potential therapeutic for treatment of glioblastoma multiforme, the most common and aggressive malignant primary brain tumor in adults. We have synthesized two diazeniumdiolate NO donors by reacting NO gas with glioma-specific targeting sequences, VTWTPQAWFQWVGGGSKKKKK (VTW) and chlorotoxin (CTX), and achieved repeatable NO release from both donors. FITC-labeled biomolecules, when incubated with glioma and control cells preferentially bound to the glioma cells and showed only minimal binding to the control cells. Additionally, tumor cell viability was significantly decreased when cells were incubated with the NO donors whereas control cell viability was not affected.     

Conversion of inhaled nitric oxide to nitrate in man.

1. Nitric oxide (NO) is potentially useful as a selective vasodilator drug in infants and adults with pulmonary hypertension. In vitro and in vivo observations demonstrate that NO may be converted to nitrate in the blood, to be further excreted into the urine. The aim of the present study was to assess quantitatively the importance of this pathway for inhaled NO in human subjects. 2. Healthy subjects inhaled 15NO (25 p.p.m.) for 1 h. The plasma and urine levels of 15NO3- were followed for 2 and 48 h, respectively. 3. The measured retention of 15NO in the lungs was 224 +/- 13 mumol, corresponding to 90 +/- 2% of the inhaled amount. Plasma 15NO3- increased during the inhalation of 15NO, to about 15 mumol l-1, and fell when inhalation of 15NO was terminated. 4. Urinary excretion of 15NO3- during the first 24 h after inhalation was 154 +/- 12 mumol. During the following 24 h another 8 +/- 2 mumol of 15NO3- appeared in the urine. 5. We conclude that conversion of inhaled NO to nitrate is a major metabolic pathway in man, covering more than 70% of its inactivation. The metabolic fate of the remaining NO inhaled requires further study.     

Release of nitric oxide after acute hypertension

We have shown that NO production, assessed by measuring changes in plasma nitrate concentration, is down-regulated when blood pressure falls. This study intended to determine first, whether NO-derived plasma nitrate varies in response to increases in blood pressure induced by different mechanical and pharmacologic stimuli, including angiotensin II and catecholamines; and second, specifically to study the interaction between angiotensin II and NO production. An intravenous infusion (4-10 min) of norepinephrine (7.5 microg/kg/min), phenylephrine (30 microg/kg/min), or angiotensin II (0.3 and 3 microg/kg/min) caused hypertension accompanied by an increase in plasma nitrate, as assessed by high-performance capillary electrophoresis. Mechanical hypertension elicited by aortic occlusion also was accompanied by an increase in plasma nitrate. Angiotensin II (0.03, 0.3, and 3 microg/kg/min, 10 min) dose-dependently increased blood pressure. The intermediate and high dose, but not the low dose, of angiotensin II increased plasma nitrate concentration. N(G)-nitro-L-arginine methyl ester (L-NAME) lowered the basal concentration of plasma nitrate, abolished the increase in plasma nitrate elicited by angiotensin II and norepinephrine, and potentiated the pressor effect of the low dose of angiotensin II, although this dose did not increase NO production. L-NAME also potentiated the pressor effects of the intermediate dose of angiotensin II. This study demonstrates that an augmented systemic production of NO, measured as an increase in plasma nitrate, takes place after acute hypertension. The results of this study suggest that an increase in NO generation occurs when angiotensin II hypertension exceeds a certain limit, below which the basal production of NO is sufficient to compensate the vasoconstriction.