Nitric oxide treatment for fulminant pulmonary hypertension

A 3 year old child with known pulmonary haemosiderosis suffered acute circulatory collapse secondary to raised pulmonary vascular resistance. Nitric oxide inhalation produced a profound improvement in circulatory parameters and gaseous exchange. Nitric oxide may have a therapeutic role in acute pulmonary hypertensive crisis.     

吸入一氧化氮逆转幼猪急性缺氧性肺动脉高压

目的 观察吸入不同浓度一氧化氮（ＮＯ）是否可逆转幼猪急性缺氧性肺动脉高压。方法 选用１０头上海种白猪。利用低氧建立急性缺氧性肺动脉高压模型。吸入不同浓度ＮＯ（０,１０,２０,４０,８０,１２０ｐｐｍ）。在各时相分别进行血液动力学指标、二氧化氮和高铁血红蛋白浓度监测。结果 吸入不同浓度ＮＯ可明显降低肺动脉平均压（ＭＰＡＰ）、肺循环阻力指数（ＰＶＲＩ）、跨肺压（ＴＰＧ）、体肺动脉压之比（Ｐｐ／Ｐｓ）、     

Nitric oxide: Biological role and clinical uses

Nitric oxide is a product of the conversion of L-arginine by the enzyme nitric oxide synthase. Nitric oxide is involved in a variety of physiological situations and is produced by many different cell types. It is involved in neurotransmission, maintenance of vascular smooth muscle tone, and cytotoxicity. Nitric oxide has been suggested to play an anti-inflammatory role by inhibiting the expression of the genes for inflammatory cytokines. The pathophysiological role of nitric oxide is also evident in a variety of diseases, including septic shock, asthma, reperfusion injury, etc. Nitric oxide, by stimulating the production of cyclic GMP, relaxes smooth muscles of the cardiovascular, respiratory, gastrointestinal, and genito-urinary systems. Recent studies have provided important information on the use of inhaled nitric oxide for the management of several diseases characterized by the presence of abnormal pulmonary vascular tone, such as persistent pulmonary hypertension of the newborn. This review addresses the biology and clinical uses of inhaled nitric oxide.     

Techniques and complementary techniques. Complementary treatments: nitric oxide, prone positioning and surfactant

The management of hypoxic respiratory failure is based on oxygen delivery and ventilatory support with lung-protective ventilation strategies. Better understanding of acute lung injury have led to new therapeutic approaches that can modify the outcome of these patients. These adjunctive oxygenation strategies include inhaled nitric oxide and surfactant delivery, and the use of prone positioning. Nitric oxide is a selective pulmonary vasodilator that when inhaled, improves oxygenation in clinical situations such as persistent pulmonary hypertension of the newborn, pulmonary hypertension associated with congenital heart disease, and acute respiratory distress syndrome (ARDS). When applied early in ARDS, prone positioning improves distribution of ventilation and reduces the intrapulmonary shunt. The surfactant has dramatically decreased mortality caused by hyaline membrane disease in premature newborns, although the results have been less successful in ARDS. Greater experience is required to determine whether the combination of these treatments will improve the prognosis of these patients.     

Residual pulmonary hypertension in children after treatment with inhaled nitric oxide: a follow-up study regarding cardiopulmonary and neurological symptoms

Inhaled nitric oxide is a potent vasodilator in acute severe pulmonary hypertension and is increasingly used as rescue treatment in intensive care algorithms aiming at reducing severe hypoxaemia in neonates and children. Although the immediate effects may seem impressive, longterm outcome regarding residual pulmonary hypertension and other sequelae has been studied in only a very few patients. The aim of the present study was to evaluate residual pulmonary hypertension, cardiopulmonary or neurological symptoms in children after treatment with inhaled nitric oxide in severely hypoxaemic and/or pulmonary hypertensive mechanically ventilated children. The study was performed in four paediatric intensive care units in university hospitals in Sweden, Norway and Australia. Patients who had received inhaled nitric oxide as part of their intensive care treatment for severe hypoxaemia and/or pulmonary hypertension, and in whom 6 mo had elapsed since treatment, were included for evaluation. Thus 36 paediatric or neonatal patients were examined for circulatory, respiratory or neurological disorders with clinical examination, echocardiography, chest X-ray and a capillary blood sample. Four patients with congenital heart disease had residual pulmonary hypertension. Nine patients were receiving bronchodilators. Sixteen patients had minor (n = 15) or moderate (n = 1) changes on a chest X-ray. One patient had a possible delay in psychomotor development. Conclusions: In spite of the severity of their primary illness, we found that the overwhelming majority of the surviving children were asymptomatic and doing well. The few residual circulatory and respiratory symptoms could be related to the initial condition.     

一氧化氮在呼吸系统疾病治疗中的应用

一氧化氮(NO)在许多疾病的病理生理过程中均发挥着重要的作用,它可选择性地舒张肺部血管,降低因缺氧等因素造成的肺毛细血管高压,改善氧合,同时还具有舒张支气管平滑肌、杀灭病原体、抗炎等作用.吸入NO在呼吸系统疾病的治疗中具有重要意义.     

一氧化氮在呼吸系统疾病治疗中的应用

一氧化氮(NO)在许多疾病的病理生理过程中均发挥着重要的作用,它可选择性地舒张肺部血管,降低因缺氧等因素造成的肺毛细血管高压,改善氧合,同时还具有舒张支气管平滑肌、杀灭病原体、抗炎等作用.吸入NO在呼吸系统疾病的治疗中具有重要意义.     

Nitric oxide in the treatment of neonatal pulmonary hypertension

This study describes the effects of nitric oxide in newborns with persistent pulmonary hypertension. We studied 9 infants with severe respiratory failure characterized by hypoxemia and pulmonary hypertension. All infants met ECMO criteria and the oxygenation index (OI) was greater than 25. Mean birth weight was 2698 -/+ 661 g and gestational age was 36.4 -/+ 2.6 weeks. Nitric oxide was administered in a Y circuit in the inspiratory line of the mechanical ventilator. Nitric oxide and NO2 concentrations were monitored with electrochemical analyzers (PACI and PACII-Draeger). Pulmonary hypertension was diagnosed with clinical and echocardiografic criteria, with detection of right to left shunt with color doppler. All patients showed a dramatic improvement in oxigenation after nitric oxide administration. The drug reduced the mean OI, which was 48.5 before its administration, to 17.7 after 30', 14.1 after 6 hours, and 10.5 after 12 hours. We observed in all patients a reduction in pulmonary vascular resistance, reversal of the right to left shunt without any effects on systemic arterial pressure. Metahemoglobin levels did not reach 1.5% in any patient. Only one out of the 9 patients died, after reversal of the pulmonary hypertension, from other complications of perinatal asphyxia. Our data show that nitric oxide is a promising drug in the treatment of neonatal pulmonary hypertension and that it may reduce the need of ECMO in severe respiratory failure.     

Exhaled and nasal nitric oxide in mechanically ventilated preterm and term newborns

AIM: Nitric oxide (NO) is an important mediator required for neonatal pulmonary circulatory adaptation and for pulmonary defence. Both deficient and excessive NO production have been proposed to play a role in neonatal lung disease. This study aimed to establish a method that allows direct measurement of exhaled and nasal NO concentrations in newborn infants who require intubation and ventilation. METHODS: A rapid-response chemiluminescence NO analyser was used. Gas was sampled from the endotracheal intubation tube, and tidal volumes and flow rates were measured. The nasal NO was sampled from the non-intubated nostril. The accuracy of the method was validated using a lung model. NO levels from six preterm and six term/near-term newborns were studied. Measurements were performed on a daily basis during the first week. RESULTS: An expiration >0.2 s in duration with a flow rate >1.7 ml s(-1) could be accurately analysed for the presence of >1 parts per billion of NO. The very preterm infants with neonatal lung disease had a different postnatal NO output pattern from the lower and upper airways compared with the ventilated term/near-term infants. CONCLUSION: A novel method for measurement of exhaled NO of an intubated newborn is presented. The possible association of exhaled NO concentration with the development of chronic lung disease remains to be studied.     

Hypertrophic pyloric stenosis and pulmonary hypertension in a neonate. A common mechanism?

Nitric oxide (NO) is an important mediator of biological functions. Absence or shortage of NO plays a role in the pathogenesis of both hypertrophic pyloric stenosis and persistent pulmonary hypertension. We present a neonate diagnosed with pulmonary hypertension after birth caused by meconiumaspiration syndrome eventually treated with extracorporal membrane oxygenation followed by hypertrophic pyloric stenosis for which a pyloromyotomy was performed. In conclusion, the association of pulmonary hypertension and pyloric stenosis has not been described before and may be explained by a lowered plasma concentration of arginine leading to deficient NO synthesis in the affected organ systems.     

Recent research on inhaled nitric oxide in preterm infants with a gestational age of <34 weeks北大核心CSCD

一氧化氮作为血管平滑肌细胞舒张的信使分子,吸入一氧化氮（inhaled nitric oxide, iNO）能够扩张肺部血管,降低肺血管阻力,从而降低肺动脉压力,而对体循环压力没有影响。国内外指南均推荐iNO用于足月儿和晚期早产儿,已证实对足月儿和晚期早产儿持续肺动脉高压和低氧性呼吸衰竭具有明显效果。但是近年来的研究显示,iNO用于胎龄<34周早产儿的超适应证治疗越来越多。该文就iNO治疗胎龄<34周早产儿的有效性、安全性、应用时机、剂量、撤离方式和与血管活性药物联合使用的国内外研究进展作一综述,以期为临床应用提供参考。     

Extracorporeal membrane oxygenation as rescue therapy for methadone-induced pulmonary edema

Opioid-induced pulmonary edema has been previously reported, but its mechanism remains unclear. The use of extracorporeal membrane oxygenation as rescue therapy for methadone-induced pulmonary edema has not been reported in the literature. We describe 2 cases of methadone ingestion complicated by pulmonary edema, acute respiratory distress syndrome, and circulatory failure successfully managed with venoarterial extracorporeal membrane oxygenation.     

Developmental changes in endothelial vasoactive and angiogenic growth factors in the human perinatal lung

Little is known of the mechanisms underlying the marked fall in pulmonary vascular resistance that occurs at birth, but changes in the expression of endothelial vasoactive and angiogenic factors during lung development might play a key role. Nitric oxide, endothelin-1, and vascular endothelial growth factor have critical effects on vascular tone and cell growth. Here, we investigated the protein expression of endothelial nitric oxide synthase, endothelin-1 and its receptors, and vascular endothelial growth factor in pulmonary necropsy samples from 14 fetuses of different gestational ages and from 5 infants. Expression of endothelin-1 and its receptor endothelin-A was strong and stable. In contrast, expression of the endothelin-B receptor was weak in early gestation, then increased markedly in mid-gestation and remained high thereafter. The expression of endothelial nitric oxide synthase and vascular endothelial growth factor fell markedly after mid-gestation and remained low thereafter. These data point to a discrepancy between maturational and functional changes in human pulmonary vascular structures. The weak perinatal expression of endothelial nitric oxide could suggest that other potent vasodilatory mediators are responsible for the marked vasodilation observed at birth.     

Effects of oxygen and nitric oxide in oxygen on pulmonary arterial pressures of children with congenital cardiac defects

Inhaled nitric oxide is a specific pulmonary vasodilator. This study was undertaken to assess the effect on pulmonary arterial pressure of administering 100% oxygen compared with nitric oxide in oxygen. Thirteen mechanically ventilated children undergoing routine cardiac catheterization for the investigation of congenital heart disease were studied. Pulmonary arterial pressures were measured during inhalation of 30% oxygen (baseline), 100% oxygen, and nitric oxide (40 parts per million) in oxygen. In addition, in six children the pulmonary/systemic blood flow ratio and pulmonary vascular resistance were calculated using oxygen content, an assumed value for oxygen uptake, and the Fick principle. Results were compared using analysis of variance and the Wilcoxon signed-rank test. Pulmonary arterial pressure decreased from a mean value of 29.5 mmHg (SD 15.1) to 25.6 mmHg (SD 9.3), p= 0.048, after increasing the inspired oxygen fraction from 0.3 to 1.0. The addition of nitric oxide caused a further reduction to 22.9 mmHg (SD 7.9), p= 0.0001. There was no change in systemic arterial pressure or heart rate during the study period, but a small increase occurred in the mean methemoglobin level (1.1% to 1.3%) p= 0.039. Changes in the pulmonary/systemic blood flow ratio and pulmonary vascular resistance (n= 6) were not significant. Nitric oxide in oxygen appears to be a more potent pulmonary vasodilator than oxygen alone in pediatric patients with congenital cardiac defects.     

延期手术对新生儿重症膈疝疗效的初步探讨

目的　探讨延期手术对新生儿重症膈疝的疗效和意义。方法　本文回顾 1985～ 2 0 0 3年复旦大学附属儿科医院收治的 2 0例重症新生儿先天性膈疝 (CDH)病例 ,其中 11例患儿进行了延期手术 ,最短 12h ,最长 5 4h ,平均2 5 3h ,3例围术期吸入一氧化氮 (NO)。以急诊手术 9例作为对照 ,对一般情况、围术期动脉血气、超声心动图结果、手术疗效和预后随访进行对照分析。结果　急诊手术组入院pH(7 19± 0 0 3)、PCO2 (18 4 3± 1 0 5 )kPa ,术后pH(7 2 4± 0 0 4 )、PCO2 (9 0 4± 4 6 6 )kPa ,术后平均呼吸机使用时间 4 0 7d ,其中 4例存活 ,5例死亡 ;延期手术组入院pH((7 19± 0 5 9)、PCO2 (6 89± 1 12 )kPa ,术前pH(7 37± 0 15 )、PCO2 (5 4 8± 2 2 6 )kPa ,都较入院有明显改善 ,术后pH(7 4 5± 0 0 2 )、PCO2 (5 0 5± 2 13)kPa ,恢复较急诊组理想 ,患者平均术后呼吸机使用时间 4 5 7d。延期组中患儿 10例存活 ,1例因术后严重肺炎无法脱离呼吸机 ,家属放弃治疗。结论　延期手术以及NO吸入等措施对于改善围手术期管理和稳定术前血流动力学指标及内环境有一定的作用 ,对降低新生儿先天性膈疝的病死率有积极的意义。     

Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery

OBJECTIVE: To test the hypothesis that cardiopulmonary bypass used for repair of ventricular septal defects and atrioventricular septal defects would decrease availability of urea cycle intermediates including arginine and subsequent nitric oxide availability. STUDY DESIGN: Consecutive infants (n = 26) undergoing cardiopulmonary bypass for repair of an unrestrictive ventricular septal defect or atrioventricular septal defect were studied. Blood samples were collected immediately before surgery, immediately after surgery, and 12 hours, 24 hours, and 48 hours after surgery. Urea cycle intermediates, including citrulline, arginine, and ornithine, were measured by amino acid analysis. Nitric oxide metabolites were measured by means of the modified Griess reaction. RESULTS: Cardiopulmonary bypass caused a significant decrease in the urea cycle intermediates arginine, citrulline, and ornithine at all postoperative time points compared with preoperative levels. The ratio of ornithine to citrulline, a marker of urea cycle function, was elevated at all postoperative time points compared with preoperative values, indicating decreased urea cycle function. Nitric oxide metabolites were significantly decreased at all postoperative time points except for 48 hours, compared with preoperative levels. CONCLUSIONS: Cardiopulmonary bypass significantly decreases availability of arginine, citrulline, and nitric oxide metabolites in the postoperative period. Decreased availability of nitric oxide precursors may contribute to the increased risk of postoperative pulmonary hypertension.     

L-精氨酸及L-硝基精氨酸对缺氧肺动脉内皮细胞内皮素的影响

目的探讨Ｌ精氨酸（一氧化氮合成的前体物质）及Ｌ硝基精氨酸（一氧化氮合酶抑制剂）对缺氧肺动脉内皮细胞内皮素１分泌及基因表达的影响。方法采用斑点杂交、Ｎｏｒｔｈｅｒｎ杂交及放射免疫分析，对常氧、缺氧、缺氧加Ｌ精氨酸及缺氧加Ｌ硝基精氨酸组的猪肺动脉内皮细胞进行了内皮素１的测定。结果缺氧能增加肺动脉内皮细胞的内皮素１的分泌及基因表达，此作用能被Ｌ精氨酸所抑制。Ｌ硝基精氨酸能增加缺氧时肺动脉内皮细胞的内皮素１分泌及基因表达。结论本实验间接提示，一氧化氮对肺动脉内皮细胞内皮素１的分泌及基因表达起调节作用     

Endothelin-A receptor blockade and inhaled nitric oxide in a porcine model of meconium aspiration syndrome

Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension.     

Inhaled nitric oxide to prevent bronchopulmonary dysplasia in preterm neonates

Bronchopulmonary dysplasia is a chronic lung disease that affects premature infants and contributes to their morbidity and mortality. With the advent of prenatal steroids and postnatal exogenous surfactant and less aggressive respiratory support, premature infants can develop chronic oxygen dependency without even acute respiratory distress. This 'new bronchopulmonary dysplasia' could be the result of impaired postnatal growth. Several experimental studies have suggested a possible role of the vascular endothelial growth factor/nitric oxide (VEGF/NO) pathway in restoring pulmonary angiogenesis and enhancing distal lung growth. The results of the clinical studies are, however, inconclusive, and it is currently unclear which subsets of premature infants might benefit from inhaled nitric oxide. Besides, severe intracranial haemorrhage and/or cystic periventricular leucomalacia may affect the most immature babies, many of whom are spared from severe initial respiratory disease. Recently, inhaled nitric oxide was shown to significantly decrease the incidence of these neurological events, and to improve the long-term outcome in a few clinical trials. At times neuroprotective, at times neurotoxic, nitric oxide is capable of divergent effects depending upon the extent of cerebral damage, the redox state of the cell, and the experimental model used. Recently, our group found that inhaled nitric oxide had remote effects including angiogenesis and maturation on the developing brain in rodent pups. Thus, we await the results of the recently completed randomised clinical trial of inhaled nitric oxide to prevent bronchopulmonary dysplasia (the European Nitric Oxide or 'EUNO' trial) where, besides the primary endpoint of chronic oxygen dependency reduction at 36 weeks' postconceptional age, long-term lung and brain will be followed-up until 7 years of age.     

Relation between plasma nitrate and mean pulmonary arterial pressure in ventricular septal defect.

BACKGROUND: Nitric oxide (NO) is known to modulate myocardial contraction and coronary tone, and its inhalation reduces pulmonary vascular resistance in patients with pulmonary hypertension. OBJECTIVES: To evaluate the pathophysiological role of NO in patients with a ventricular septal defect (VSD). PATIENTS: Twenty-nine children with VSD, nine of whom had undergone VSD closure surgery, and 14 patients with Kawasaki disease. The mean age of the VSD patients was 3.1 years (range, 2 months to 9 years). METHODS: Using high performance liquid chromatography, nitrate (a more stable NO oxidation product) was measured in plasma specimens of the patients undergoing cardiac catheterisation. RESULTS: Nitrate concentrations in the pulmonary artery bore a significant relation to mean pulmonary artery pressure, pulmonary to systemic systolic pressure ratio, and pulmonary to systemic flow ratio. CONCLUSIONS: The concentration of nitrate was in proportion to the increment in intravascular or cardiac pressure, indicating that endogenous NO is upregulated as a compensatory homeostatic attempt to reduce pulmonary pressure and blood flow.