Correlations of lung morphology, pulmonary vascular resistance, and outcome in children with congenital heart disease.

Pulmonary vascular resistance was measured in air, oxygen, and after administration of vasodilators in 14 children with pulmonary hypertension and congenital heart disease. Lung morphology was examined by light microscopy and assessed quantitatively. In this selected group of patients (a) medial muscle thickness of greater than 20% in the intra-acinar arteries and Heath-Edwards changes of I or II were significantly associated with perioperative death from pulmonary complications after cardiac surgery; (b) children with lower percentage medial muscle thickness had a higher baseline resistance (r = -0.84) associated with Heath-Edwards grade III or higher changes (most of these patients were not offered corrective surgery); (c) when the lowest pulmonary vascular resistance was less than 3 units, Heath-Edwards grading was I or II (n = 4). When the pulmonary vascular resistance was greater than 6 units, however, there was no direct correlation with Heath-Edwards grading (n = 9). Four patients with a resistance of greater than 6 units had only grade I or II changes. Three had a medial muscle thickness above 20%, and were among those who died at or soon after operation. It is concluded that (a) patients with a lowest pulmonary vascular resistance of greater than 6 units have a bad prognosis whatever their lung morphology; and (b) some patients with Heath-Edwards grade I or II will have a high resistance (this group has a high medial muscle mass and a poor prognosis and would not be detected by Heath-Edwards grading alone).     

Effect of inhaled nitric oxide on pulmonary function in cystic fibrosis.

Concentrations of nitric oxide (NO) have been found to be reduced in both the upper and lower airway of patients with cystic fibrosis (CF). As NO modulates bronchomuscular tone, low NO levels may contribute to the obstructive lung disease in these patients. To assess whether increasing inspiratory NO concentrations has any impact on lung function, we have studied 13 CF patients aged 14-38 years in a clinically stable condition and nine healthy controls. NO was applied via a mixing chamber for 5 min with NO concentrations of 100 parts per billion, 1 and 40 parts per million. Spirometry was performed at baseline and after inhalation on each occasion. There were no clinical side-effects at any NO concentration and no changes in oxygen saturation were observed. Lung function remained unchanged in all subjects throughout the study period. Sputum nitrate and nitrite concentrations before and after inhalation of high NO concentrations (40 ppm) in eight CF patients did not show any significant changes, even though a tendency to higher nitrate levels was observed (399 +/- 231 vs. 556 +/- 474 mumol l-1). Therefore, inhaled NO at either the physiological levels present in the upper airway of normal individuals or those used therapeutically to treat pulmonary hypertension has no immediate effect on bronchomuscular tone in patients with cystic fibrosis.     

Correlations of lung morphology, pulmonary vascular resistance, and outcome in children with congenital heart disease

Pulmonary vascular resistance was measured in air, oxygen, and after administration of vasodilators in 14 children with pulmonary hypertension and congenital heart disease. Lung morphology was examined by light microscopy and assessed quantitatively. In this selected group of patients (a) medial muscle thickness of greater than 20% in the intra-acinar arteries and Heath-Edwards changes of I or II were significantly associated with perioperative death from pulmonary complications after cardiac surgery; (b) children with lower percentage medial muscle thickness had a higher baseline resistance (r = -0.84) associated with Heath-Edwards grade III or higher changes (most of these patients were not offered corrective surgery); (c) when the lowest pulmonary vascular resistance was less than 3 units, Heath-Edwards grading was I or II (n = 4). When the pulmonary vascular resistance was greater than 6 units, however, there was no direct correlation with Heath-Edwards grading (n = 9). Four patients with a resistance of greater than 6 units had only grade I or II changes. Three had a medial muscle thickness above 20%, and were among those who died at or soon after operation. It is concluded that (a) patients with a lowest pulmonary vascular resistance of greater than 6 units have a bad prognosis whatever their lung morphology; and (b) some patients with Heath-Edwards grade I or II will have a high resistance (this group has a high medial muscle mass and a poor prognosis and would not be detected by Heath-Edwards grading alone).     

吸入伊洛前列素在儿童先天性心脏病肺血管扩张试验中的应用

目的:该研究在心导管检查中通过对先天性心脏病(CHD)合并肺动脉高压(PAH)儿童,吸入伊洛前列素前后的血流动力学参数的测定,评价吸入伊洛前列素在CHD相关性PAH儿童急性肺血管扩张试验的安全性、有效性。方法:研究选择2007年6月至2010年5月,于北京安贞医院小儿心脏科住院的左向右分流型CHD合并重度PAH患儿,所有患儿行左、右心导管检查,并采用雾化吸入伊洛前列素,监测吸药前后血流动力学参数改变及不良反应。结果:该研究入选43例左向右分流型CHD合并重度PAH患儿,年龄(8.52±4.76)岁。吸入伊洛前列素后肺动脉平均压由(77.14±12.14)mmHg(1 mmHg=0.133 kPa)降至(69.35±12.14)mmHg(P<0.05);肺体循环血流量比值(Qp/Qs)由1.80±1.26升至3.06±2.90(P<0.05);肺血管阻力指数(PVRI)下降约5 Wood unit.m2〔吸入前(14.51±8.46)Wood unit.m2,吸入后(9.58±7.43)Wood unit.m2,P<0.05),体循环血压无明显变化〔吸入前(83.16±13.69)mmHg,吸入后(83.09±11.03)mmHg,P>0.05〕。以吸入伊洛前列素后PVRI较基础水平下降至少20%以上作为急性肺血管扩张试验阳性标准。肺血管反应阳性患儿31例,占72%,阴性反应患儿(PVRI下降<20%)12例,占28%。结论:对左向右分流型CHD合并重度PAH儿童在心导管检查中吸入伊洛前列素可明显降低肺血管阻力,体循环血压无明显变化,无明显不良反应发生,可作为安全有效的急性肺血管扩张试验的用药。     

Maturational changes in ovine pulmonary vascular responses to inhaled nitric oxide

Developmental changes in modulation of pulmonary vasomotor tone by endothelium-derived nitric oxide (EDNO) may reflect maturational differences in endothelial synthesis of and/or vascular smooth muscle response to nitric oxide. This study sought to determine whether pulmonary vascular sensitivity and responsiveness to nitric oxide change during newborn development, and whether this is related to changes in guanylate cyclase activity. Pulmonary artery dose-responses to inhaled nitric oxide (iNO, 0.25-100 parts per million) were measured in hypoxic, indomethacin-treated, isolated lungs from 1-day (1-d)- and 1-month (1-m)-old lambs. The lungs of 1-m-old lambs were ventilated with 4% (oxygen) O2, and lungs of 1-d-old lambs were ventilated with either 4% or 7% O2 in order to achieve similar stimuli or vasomotor tone. Cyclic guanosine monophosphate (cGMP) concentrations in the perfusate were measured at iNO concentrations of 0, 5, and 100 parts per million (ppm). Basal and stimulated pulmonary guanylate cyclase activity was also measured in lung extracts in vitro. The effects of iNO were similar in both 1-d groups, even though baseline hypoxic tone was significantly higher in 1-d lungs ventilated with 4% O2 than with 7% O2. Furthermore, both the 1-d 7% O2 and 1-d 4% O2 lungs exhibited greater responsiveness and sensitivity to iNO than 1-m lungs. Perfusate cGMP concentrations and soluble guanylate cyclase activity were higher under stimulated than basal conditions, but neither differed statistically between 1 d and 1 m. These data suggest that pulmonary vascular responsiveness and sensitivity to nitric oxide decrease with age, but the mechanisms underlying these maturational changes require further investigation.     

一氧化氮和纯氧对重度肺动脉高压者肺阻力的影响

目的 :评价吸入低浓度一氧化氮 (NO)和纯氧 (O2 )在伴有重度肺动脉高压的先天性心脏间隔缺损患者术前的应用价值。方法 :对 1 3例患者 ,平均年龄 (2 3± 9)岁 ,在术前右心导管检查中分别吸入 NO(40μl/ L )和 O2 行降压试验。结果 :基础状态下肺阻力重度增加的患者 ,NO和 O2 均明显降低肺阻力 ,但下降率差别不显著。而肺阻力轻、中度增加者 ,下降率差异极显著 ,分别为52 %和 5% (P <0 .0 0 1 )。结论 :NO可有效地解除功能因素参与的肺血管收缩 ,可用于先天性心脏病患者术前肺血管功能状态的评价 ,其效果明显优于 O2 。     

Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with congenital heart defects and pulmonary arterial hypertension.

BACKGROUND: It was previously demonstrated that in adults with congenital heart disease and pulmonary arterial hypertension and/or the Eisenmenger syndrome, the pulmonary circulation remained responsive to inhaled nitric oxide (iNO). We wanted to evaluate whether the responsiveness to iNO was related to mid-term outcome in these patients. METHODS: In 21 consecutive patients, total pulmonary vascular resistance (TPR) was measured at baseline, after 5 min iNO (80 ppm), and after NO withdrawal. Patients were considered responders when TPR was reduced by at least 20% during NO inhalation or when TPR increased by more than 10% after NO withdrawal. Responders and non-responders were followed prospectively and the primary endpoint of the study was cardiopulmonary death, the secondary endpoint the combination of death, need for treatment with prostacyclin or heart-lung transplantation. Kaplan-Meier survival curves for both groups were plotted and compared using log rank testing. RESULTS: Ten patients were considered responders (four male, median age 25 years, Q1 19 and Q3 66 years), while 11 patients did not respond (two male, median age 27 years, Q1 18 and Q3 40 years). The median follow-up time of the total group was 5.0 years (Q1 3.2 and Q3 5.7 years). Four of the non-responders died a cardiovascular death; none of the responders died. The difference in survival between responders and non-responders was statistically significant. For the secondary endpoint, no significant differences were found between both groups. CONCLUSIONS: The responsiveness to inhaled NO in adult patients with pulmonary arterial hypertension and/or the Eisenmenger syndrome is related to mid-term outcome. These findings might be important for risk stratification and the choice of treatment in this specific patient population.     

Two-stage procedure for pulmonary vascular obstructive disease in Down syndrome with congenital heart disease.

BACKGROUND: Down syndrome patients are characterized by early progression of pulmonary vascular obstructive disease because of insufficient thickness of the pulmonary arterial media. For those with congenital heart disease (CHD) associated with pulmonary hypertension (PH), a 2-stage procedure of pulmonary artery banding (PAB) and then intracardiac repair (ICR) in early infancy is performed to prevent such pulmonary vascular diseases in early infancy. METHODS AND RESULTS: The subjects were 16 patients with Down syndrome who underwent lung biopsy during PAB and ICR. PAB was planned to be performed in early infancy and ICR approximately 1 year later. Efficacy of the 2-stage procedure was retrospectively examined with reference to pulmonary vascular disease and pulmonary diseases. The index of pulmonary vascular disease at PAB fulfilled the indication for ICR, and it was significantly lower at ICR than at PAB (p=0.0469); furthermore, PAB prevented progression of pulmonary diseases. CONCLUSIONS: The results of the lung biopsies support the safety of the 2-stage procedure and show that it is effective for Down syndrome patients with CHD and PH.     

Comparison of the acute pulmonary vasodilating effect of beraprost sodium and nitric oxide in congenital heart disease.

BACKGROUND: Congenital heart disease patients who have pulmonary hypertension (PH) require an evaluation for pulmonary vascular reactivity before surgical repair. In the present study the acute pulmonary vasodilating effects of 100% oxygen (O2), beraprost sodium (BPS) and 40 ppm inhaled nitric oxide (iNO) during cardiac catheterization were compared. METHODS AND RESULTS: There were 90 patients who underwent cardiac catheterization for evaluation of PH (mean age, 16.5+/-16 years). The baseline mean pulmonary artery (mPA) pressure was 69.6+/-14.8 mmHg and the pulmonary arteriolar resistance (Rpa) was 13.8+/-8.3 Wood unit m2. Change in pulmonary vascular reactivity was defined as a decrease in mPA or Rpa>20% from baseline. The response to 100%O2, iNO and BPS during cardiac catheterization was 84%, 72.7% and 64%, respectively. Pair comparisons among each hemodynamic parameter showed no difference between the acute vasodilating effect of BPS and iNO. In some patients BPS showed a stronger effect than iNO in lowering Rpa. CONCLUSIONS: BPS has a similar pulmonary vasodilating effect to iNO and can be used as an acute pulmonary vasodilating agent during cardiac catheterization with potential benefits over iNO.     

Peripheral vasodilatory dysfunction in adult patients with congenital heart disease and severely elevated pulmonary vascular resistance

Several studies have demonstrated that pulmonary vascular abnormalities precede alterations in aortic circulation downstream in animal models of heart failure. The relationship between increased pulmonary vascular resistance (PVR) and agonist-induced limb vasodilatory response remains unknown in patients with congenital cardiovascular shunt lesions (CSL). The authors hypothesized that patients with CSL and severely elevated PVR will show a defective vasomotor response in the peripheral vascular bed. To examine this hypothesis we measured forearm blood flow (FBF) responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. The values for these FBF responses were compared with PVR in adult patients with CSL (n=20) and healthy age- and sex-matched controls (n = 15). When patients with CSL were divided into 2 subgroups by median value of PVR, in the lower PVR subgroup, acetylcholine-induced FBF changes were selectively and significantly lower than in the healthy control group (p <0.05). In the higher PVR subgroup, FBF responses to both acetylcholine and sodium nitroprusside were significantly blunted compared to healthy controls (both p < 0.01). In addition, when FBF changes above baseline for each dose of acetylcholine and sodium nitroprusside were cumulated and used as acetylcholine response and sodium nitroprusside response, the sensitivity and specificity for identifying patients with Eisenmenger's type of CSL was 100% and 80% by acetylcholine response, and 67% and 80% by sodium nitroprusside response, respectively. In conclusion, adult CSL patients with elevated PVR and severe pulmonary arterial hypertension showed generalized vasodilator dysfunction in the forearm vasculature. This result suggests that upper limb resistance vessel dysfunction may be an indicator for advanced stage of adult patients with CSL.     

Effect of inhaled steroid therapy on exhaled nitric oxide and bronchial responsiveness in children with asthma.

Inhaled steroid therapy is reported to reduce the level of exhaled nitric oxide (eNO), but the effects of inhaled corticosteroids (ICS) on bronchial hyperresponsiveness (BHR) have been controversial. The aim of this study was to determine the effects of ICS on the relationship between eNO and BHR. Twenty-six children with asthma were recruited, including 14 children who were receiving ICS (ICS group) and 12 who were not (ICS-naive group). The fractional exhaled nitric oxide concentration (FE(NO)) was examined by the recommended online method. To evaluate BHR, an acetylcholine challenge test was performed. In the ICS-naive group, FE(NO) was significantly correlated with PC20 (p < 0.05, r = -0.70), but not in the ICS group. In conclusion, FE(NO) was significantly correlated with BHR in the ICS-naive group, but this relationship was not present in the ICS group. Our results suggest that the use of ICS should be taken into consideration when evaluating the relation between BHR and airway inflammation.     

Oral hydralazine in patients with pulmonary vascular disease secondary to congenital heart disease

Two patients with pulmonary vascular obstructive disease secondary to congenital heart disease were evaluated hemodynamically before and during oral hydralazine therapy. Both patients were assessed postoper-atively and had no significant residual shunts. Pulmonary vascular resistance failed to decrease, and an increase in pulmonary arterial pressure occurred because of increased cardiac output secondary to systemic arteriolar dilatation. These responses were sufficiently consistent to warrant a warning against the use of oral hydralazine except under controlled conditions in patients with secondary pulmonary vascular obstructive disease.     

Impact of pulmonary vascular resistances in heart transplantation for congenital heart disease

Congenital heart disease is one of the major diagnoses in pediatric heart transplantation recipients of all age groups. Assessment of pulmonary vascular resistance in these patients prior to transplantation is crucial to determine their candidacy, however, it is frequently inaccurate because of their abnormal anatomy and physiology. This problem places them at significant risk for pulmonary hypertension and right ventricular failure post transplantation. The pathophysiology of pulmonary vascular disease in children with congenital heart disease depends on their pulmonary blood flow patterns, systemic ventricle function, as well as semilunar valves and atrioventricular valves structure and function. In our review we analyze the pathophysiology of pulmonary vascular disease in children with congenital heart disease and end-stage heart failure, and outline the state of the art pre-transplantation medical and surgical management to achieve reverse remodeling of the pulmonary vasculature by using pulmonary vasodilators and mechanical circulatory support.     

吸入一氧化氮治疗肺血栓栓塞症的临床研究进展

吸入一氧化氮可以降低肺血栓栓塞症患者的肺血管阻力,降低肺动脉高压,解除右心室后负荷;治疗肺血栓栓塞症患者血栓手术后或肺动脉内肺血栓动脉内膜切除术后所形成的肺水肿、再灌注肺损伤和持续肺动脉高压等并发症;改善患者肺通气／血流失调,解除支气管痉挛,改善氧分压;抑制患者血小板活性和聚集,延长出血时间;对心肌损害和心功能的保护作用。吸入一氧化氮对患者有一定的毒副作用,一氧化氮吸入装置的不完善也对一氧化氮吸入在临床上的应用有一定的影响。对这些知识的全面认识,将对临床吸入一氧化氮治疗肺血栓栓塞起到积极的作用。