Paradoxical Relationship Between B-type Natriuretic Peptide and Pulmonary Vascular Resistance in Patients with Ventricular Septal Defect and Concomitant Severe Pulmonary Hypertension

B-type natriuretic peptide (BNP) reflects volume overload on left ventricle and pulmonary hypertension (PH) in patients with ventricular septal defect (VSD). Pulmonary vascular resistance (PVR) has been reported to correlate positively with BNP in VSD patients with various degrees of PH. We aimed to investigate the relationship between PVR and BNP in VSD patients with severe PH. We examined 24 subjects with VSD concomitant severe PH aged from 2 months to 17 years (median: 4 months). The ratio of pulmonary to systemic pressure (Pp/Ps), the ratio of pulmonary to systemic flow (Qp/Qs), the ratio of pulmonary to systemic resistance (Rp/Rs), and PVR were determined by cardiac catheterization. PVR and Rp/Rs ranged from 1.6 to 15.5 (mean: 5.7 ± 3.9) Wood unit · m² and 0.1 to 0.8 (mean: 0.4 ± 0.2), respectively. BNP ranged from 5.5 to 69 (mean: 31 ± 19) pg/ml. Negative correlations were observed between BNP and PVR (r = -0.56, p = 0.004) and BNP and Rp/Rs (r = -0.51, p = 0.01). BNP was significantly lower (<10 pg/ml) in VSD patients with Eisenmenger physiology as compared with the others (p = 0.003). We should draw attention to evaluate BNP values in VSD patients with severe PH.     

Inhalation of nebulized nitroglycerin in dogs with experimental pulmonary hypertension induced by U46619

BACKGROUND: Pulmonary hypertension (PH) causes mortality in some congenital and acquired heart and lung diseases. However, inhalation of NO gas requires complicated and expensive instruments and elaborate preparations to avoid toxic gas administration. We tested the effectiveness and safety of inhaled nebulized nitroglycerin (Neb-NTG) in dogs with experimental PH. METHODS: Experimental PH was induced by continuous infusion of a thromboxane analog (U46619). The U46619 infusion rate was adjusted to maintain a systolic pulmonary artery pressure (PAP) at 40 mmHg in 10 anesthetized and mechanically ventilated dogs. Then, 20 micrograms/kg of NTG liquid nebulized by compressed air was inhaled. RESULTS: After infusion of U46619, the systolic, diastolic and mean PAP increased by 119%, 228% and 169%, respectively, and the systolic, diastolic and mean systemic arterial pressures (SAP) increased by 19%, 29% and 23%, respectively. The systolic pulmonary to systemic pressure ratio (Pp/Ps) and mean Pp/Ps increased by 83% and 113%, respectively, and the pulmonary vascular resistance (PVR), systemic vascular resistance (SVR) and pulmonary to systemic resistance ratio (Rp/Rs) increased by 341%, 100% and 145%, respectively. After inhalation of Neb-NTG in dogs with experimental PH, systolic, diastolic and mean PAP and PVR decreased by 25 +/- 4, 26 +/- 11, 25 +/- 9 and 31 +/- 21%, respectively. There were no significant changes in systolic, diastolic and mean SAP, SVR, cardiac output and plasma methemoglobin concentrations. The systolic and mean Pp/Ps decreased by 18 +/- 7 and 20 +/- 7%, respectively. The Rp/Rs decreased by 25 +/- 13%. CONCLUSIONS: The results of this study demonstrate that Neb-NTG is an effective and selective pulmonary vasodilator and may offer a new therapeutic option for PH.     

肺动脉高压时肺小动脉弹性蛋白的表达变化

研究脉动脉压力对肺小动脉璧原弹性蛋白表达与颁的影响以帮助阐明先天性心脏病（先心病）肺动脉高压（肺高压）肺血管重建的发病机制。将１５例患儿分为对照组（组１）、先心病高肺血流组（组２）及先心病肺高压组（组３）。用免疫组化技术研究弹性蛋白在肺小动脉璧的含量与分布以了解弹性蛋白的合成情况;用原位杂交技术在转录水平研究肺小动脉间性蛋白ｍＲＮＡ的表达分布。结果：各组患儿间年龄比较无差异。组２、组３间肺动脉压力     

Effects of prostacyclin and milrinone on pulmonary hemodynamics in newborn lambs with persistent pulmonary hypertension induced by ductal ligation

Prostacyclin (PGI(2)) stimulates adenyl cyclase to synthesize cAMP within the vascular smooth muscle resulting in vasodilatation. Milrinone inhibits cAMP clearance by phosphodiesterase type III. We studied the dose response of pulmonary and systemic hemodynamics to intratracheal (IT) PGI(2) in newborn lambs with pulmonary hypertension (PH) and whether intravenous milrinone potentiate these effects. IT-PGI(2) at varying doses was administered to lambs with PH induced by prenatal ductal ligation. IT-PGI(2) doses were repeated in the presence of intravenous milrinone (bolus-100 microg/kg followed by infusion at 1 microg/kg/min). Increasing doses of IT-PGI(2) significantly decreased mean pulmonary arterial pressures (PAP) and pulmonary vascular resistance (PVR) and increased pulmonary blood flow (PBF). Intravenous milrinone by itself produced a significant reduction in PVR and a significant increase in PBF. Intravenous milrinone significantly shortened the onset, prolonged the duration and degree of pulmonary vasodilation produced by PGI(2). We conclude that intravenous milrinone potentiates the pulmonary vasodilator effects of PGI(2) at lower doses.     

Assessment of left ventricular function in secundum atrial septal defect: evaluation by determination of volume, pressure, and external systolic time indices.

Left ventricular function and volume data from 17 control subjects and 27 young patients with secundum atrial septal defect (ASD) without overt left or right ventricular failure were compared. ASD patients were subdivided in low shunt (Qp/Qs less than 2.0) and high shunt (Qp/Qs larger than or equal to 2.0) groups. Mean left ventricular (LV) stroke volume was significantly less in ASD patients (46 +/- 16 ml/m2 in the low shunt and 44 +/- 9 ml/m2 in high shunt group) compared with control patients (51 +/- 13 ml/m2, P less than 0.01 and P less than 0.02, respectively). There was no significant difference in mean left ventricular end-diastolic volume (LVEDV) between any group of patients (control subjects 67 +/- 17 ml/m2; low shunt ASD 66 +/- 17 Ml/m2, and high shunt ASD 62 +/- 12 ml/m2). High shunt ASD had a significantly lower cardiac index compared with control patients (5.0 liters/min/m2 vs. 5.9 liters/min/m2, P less than 0.02). Both low shunt and high shunt ASD showed significantly lower stroke work indices than control subjects (42 +/- 13 GmM/m2 and 37 +/- 8 GmM/m2 compared with 51 +/- 14 GmM/M2 , P less than 0.05 and P less than 0.001, respectively) but only the high shunt group had a significantly lower peak systolic pressure (94 +/- 12 mm Hg vs. 109 +/- 11 mm Hg for control patients, P less than 0.01). There was no significant difference between the control and ASD groups in LV end-diastolic, mean right atrial, right ventricular end-diastolic, and pulmonary pressures. External systolic time intervals were compared in 5 control and 12 ASD patients. There was no significant difference between the two groups of patients in absolute values or indices for pre-ejection period, ejection time, or electromechanical systole. However, the ratio of the pre-ejection period index to left ventricular ejection time index (PEPI/LVETI) was significantly higher in ASD patients (P less than 0.05). In young subjects with large shunt ASD, certain indicators of left ventricular function are depressed. Evaluation of PEPI/LVETI may allow noninvasive determination of LV function.     

Spontaneous closure of perimembranous ventricular septal defect after school age

Background: The number of studies of long‐term follow up to adolescence is very low on spontaneous closure (SC) of perimembranous ventricular septal defects (P‐VSD) in children not undergoing surgical closure because of small left‐to‐right shunting. Methods: Seventy patients with a P‐VSD with pulmonary‐to‐systemic flow ratio (Qp/Qs) < 1.7 underwent cardiac catheterization at the age of 2–10 years (mean, 5.1 years). Excluding 22 patients who dropped out by 15 years, 48 were selected. Qp/Qs ranged from 1.00 to 1.68 (mean, 1.17). The average follow‐up period of 37 patients excluding the SC patients was 17.8 years. They were classified according to Qp/Qs into three groups: group I, 1.4 ≤ Qp/Qs < 1.7; group II, 1.2 ≤ Qp/Qs < 1.4; and group III, 1.0 ≤ Qp/Qs < 1.2. Results: SC occurred in 11 patients (23%). SC rates in group I and II were lower than those in group III (I, 0/8 0%; II, 1/10 10%; III, 10/30 33%). In 23 patients (48%), an aneurysm of the ventricular membranous septum (AVMS) was detected, but no significant relationship was found between the presence of AVMS and SC rate. Conclusions: SC occurred in 23% of patients with a P‐VSD of Qp/Qs < 1.7 up to adolescence. But a P‐VSD of Qp/Qs ≥ 1.2 showed no tendency to close spontaneously. The factor most influencing SC of P‐VSD after school age seemed to be the shunt ratio.     

Hemodynamic consequences of inotropic support with digoxin or amrinone in lambs with ventricular septal defect

Inotropic support with digoxin is commonly used in patients with left ventricular volume overload due to ventricular septal defect (VSD). However, the hemodynamic consequences of inotropic agents with VSD have not been experimentally explored. We studied two inotropic agents, digoxin and amrinone, in chronically instrumented lambs with left ventricular volume overload due to a surgically created VSD. Intravenous digoxin (40 micrograms/kg) produced serum levels of 3.5 +/- 0.9 ng/ml (mean +/- SD) in seven lambs 60 min after administration, reduced the heart rate by 16% (172 to 149 beats/min, p less than 0.05), increased the stroke volume 16% (29.8 to 34.5 ml/beat, p less than 0.05) but did not significantly alter the systemic flow index (Qs), the pulmonary flow index (Qp), or the volume of left to right shunt (QL-R, 6.74 to 6.77 liter/min/m2). The mean left atrial pressure (LA) was unchanged (17.6 versus 17.1 mm Hg) following digoxin. Chronic digoxin use in four lambs for 4 days (25 +/- 8 micrograms/kg/8 h) produced trough serum levels of 1.2 +/- 0.2 ng/ml. There was no additional hemodynamic effect compared to acute digoxin, the Qp/Qs ratio was unchanged (3.10 versus 3.08) and evidence of left ventricular volume overload (LA - 14.0 versus 13.4) was unchanged. Amrinone lowered the systemic resistance index in a dose dependent fashion. The peak reduction of 20% (25.3 to 20.3 U/m2, p less than 0.01) occurred at 20 min after an intravenous (3 mg/kg) bolus in seven lambs. The Qs increased from 2.58 to 3.10 liter/min/m2 (p less than 0.01). The Qp was unchanged, thus the Qp/Qs ratio was lowered by 16% (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ductus arteriosus ligation and alveolar growth in preterm baboons with a patent ductus arteriosus

Premature newborn baboons [125 d (67%) gestation], exposed to a moderate-size patent ductus arteriosus (PDA) [pulmonary-to-systemic blood-flow-ratio (Qp/Qs) = 1.8] for 14 d, have impaired pulmonary function and arrested alveolar development and surface area when compared with age matched fetuses (140 d gestation). Pharmacologic closure of the PDA reduces the detrimental effects of preterm delivery on pulmonary function and surface area. We used preterm baboons (delivered at 125 d gestation and ventilated for 14 d) to study the effects of surgical PDA ligation on pulmonary function and alveolar surface area. After ligation (on day of life 6), ligated animals had lower Qp/Qs ratios [Qp/Qs (ligated, n = 10) = 1.00 +/- 0.04; (nonligated, n = 12) = 2.05 +/- 0.17; mean +/- SD] and higher systemic blood pressures than nonligated control animals. Ventilation and oxygenation indices did not differ between the groups, during either the pre- or postoperative periods. Alveolar surface area measurements were made by digital image analysis and compared with measurements made from fetal lungs at 125 d (n = 6) and 140 d (n = 7) gestation. PDA ligation failed to improve the postnatal arrest in alveolar surface area. In contrast with pharmacologic closure of the PDA, surgical closure failed to improve either pulmonary function or alveolar surface area in baboons with a moderate PDA shunt.     

硫化氢对大鼠高肺血流性肺血管重构机制影响的研究

目的 探讨硫化氢（hydrogen sulfide,H2S）对大鼠高肺血流性肺血管重构的影响及其机制。方法 雄性SD大鼠32只,随机分为分流组、分流＋硫氢化钠（sodiumhydrosulfide,NaHS）组、对照组和对照＋NaHS组。分流组和分流＋NaHS组大鼠经腹主动脉一下腔静脉穿刺建立高肺血流动物模型。用敏感硫电极法测定大鼠肺组织H2S含量;计算大鼠肺肌型动脉（muscularized artery,MA）的百分比及MA的相对中膜厚度（relativemedialthickness,RMT）;应用蛋白质免疫印迹技术（Westernblot）定量分析大鼠肺动脉平滑肌细胞增殖细胞核抗原（proliferation cell nuclear antigen．PCNA）、细胞外信号调节激酶（extracellular signal-regulated kinase,ERKl）、磷酸化细胞外信号调节激酶（phosphorylation extracellular signal-regulated kinase,P-ERK）;应用免疫组织化学法对PCNA进行定位及半定量分析。结果 分流11周后,与对照组比较,分流组大鼠肺组织H2S含量降低（P〈0．05）、肺动脉MA百分比及RMT升高（P〈0．05）;肺动脉PCNA阳性百分比、P-ERK／ERK1增高（P均〈0．01）。与分流组比较,分流＋NaHS组MA百分比及RMT低于分流组（P〈0．01）;肺动脉PCNA阳性百分比、肺动脉P-ERK／ERK1低于分流组（P〈0．01）。结论 H2S通过丝裂原活化蛋白激酶（mitogen-activated protein kinase,MAPK）／ERK信号转导通路调节大鼠高肺血流性肺血管重构。     

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??Objective??To explore the preventive effect of regular doses of captopril on the pulmonary arterial hypertension associated with ventricular septal defect??VSD?? and its mechanism. Methods??Forty cases of children with VSD in accordance with the inclusive criteria??who were hospitalized in Chengdu Women and Children’s Central Hospital from July 2013 to July 2015 ??were collected and randomly divided into blank control group??n??20??and captopril intervention group??n??20??. Plasma MMP-9 and TIMP-1 were examined by using ELISA??and PASP??the Qp/Qs and right ventricular Tei index were measured by cardiac color Doppler ultrasound at 0 week??1 week??4 weeks??8 weeks??and 12 weeks respectively??side effects in captopril intervention group were also observed. Results??PASP??the Qp/Qs??right ventricular Tei index??plasma MMP-9 and TIMP-1 level in blank control group were increased over time??the same indexes in captopril intervention group were decreased??the changing trend of two groups had statistically significant difference??all P??0.05??. The indexes were of no difference between the two groups at 0 week??all P??0.05????PASP and right ventricular Tei index in captopril intervention group were lower than blank control group at 1 week??4 weeks??8 weeks??and 12 weeks??all P??0.05????the Qp/Qs plasma??MMP - 9 and TIMP - 1 level in captopril intervention group were lower at 4 weeks??8 weeks??and 12 weeks??all P??0.05??. No side effects were found in captopril intervention group during follow-up. Conclusion??Oral regular doses of captopril in the VSD children undergoing elective surgery may reduce pulmonary vascular remodeling and prevent pulmonary hypertension in order to achieve the best age at surgery??one of the mechanisms might be improving indexes of PASP??right ventricular Tei index and the Qp/Qs by reducing the plasma MMP 9 and TIMP - 1 level.     

Growth parameters and endocrine function in relation to echocardiographic parameters in children with ventricular septal defect without heart failure.

To determine the effect of ventricular function, size of ventricular septal defect (VSD), and endocrine function on linear growth in children with VSD, we studied 88 children with VSD over a period of 1 year. Growth was assessed by determining the height standard deviation scores (HtSDS) and growth velocity (GV) every 4 months. Two hundred age-matched normal children served as controls for the growth data. Endocrine evaluation was performed in 30 randomly selected children with VSD, and 20 age-matched children with constitutional delay of growth (CSS). Growth hormone (GH) response to clonidine provocation was evaluated and circulating free thyroxine (FT4) and insulin-like growth factor-I (IGF-I) concentrations measured. Echocardiographic evaluation of the different cardiac parameters including shunt size and shunt fraction (Qp/Qs) was performed using a colour-coded echodoppler. The HtSDS, body mass index (BMI), and mid-arm circumference (MAC) of children with VSD were significantly decreased compared to those for the normal control group. The dietary intake evaluated by the recall method, appeared to be adequate in the majority of these children (83/88). IGF-I concentrations were reduced in children with VSD (87.5 +/- 29 ng/ml) versus normal age-matched children (169 +/- 42 ng/ml). Basal and clonidine-stimulated GH concentrations were significantly higher in children with VSD (4.6 +/- 2.1 microg/l and 28.8 +/- 7.9 microg/l respectively) versus controls (17.8 +/- 4.2 microg/l). In these patients (n = 88) the HtSDS was correlated negatively with the size of the shunt (r = -0.793, p < 0.001), shunt fraction (Qp/Qs) (r = -0.76, p < 0.001), pulmonary mean gradient (r = -0.4, p = 0.006), and pulmonary maximum velocity (r = -0.32, p = 0.02). Growth velocity (GV) was correlated negatively with pulmonary maximum gradient (r = -0.3, p = 0.02), pulmonary maximum velocity (r = -0.37, p = 0.007), and pulmonary stroke volume (Qp) (r = -0.345, p = 0.01). The BMI and IGF-I concentrations were correlated significantly with the size of the shunt (r = -0.453, p < 0.01), Qp/Qs (r = -0.432, p < 0.01), HtSDS (r = 0.565, p < 0.01), and BMI (r = 0.435, p < 0.01). It appears that in patients with VSD, the size of the left-to-right shunt and the abnormal hemodynamics in the pulmonary circulation are important factors in the etiology of impaired growth. It is suggested that the hypermetabolic status of these patients compromise nutrition and this decreases IGF-I synthesis with subsequent slowing of linear growth and weight gain.     

Nitric oxide-related compounds in patients with congenital heart defects and pulmonary hypertension

BACKGROUND: The relationship between blood levels of nitric oxide (NO)-related compounds in patients with congenital heart defects (CHD) and degree of pulmonary hypertension (PH) has not yet been described. METHODS: Thirty-six patients (aged 6 months to 19 years) with CHD were divided into three groups on the basis of their hemodynamic characteristics: group 1 (control, n = 5), left-to-right shunt (-) without PH (pulmonary to systemic artery peak pressure ratio, Pp/Ps < 0.4); group 2 (n = 14), left-to-right shunt (+) without PH; group 3 (n = 17), left-to-right shunt (+) with PH (Pp/Ps > 0.4). Blood samples were obtained from the right atrium, pulmonary artery, left atrium or pulmonary capillary wedge and aorta during cardiac catheterization. All NO-related compounds in whole blood were measured by chemiluminescent assay using Sievers NO analyzer. RESULTS: The sampling site had no significant impact on NO-related compound levels. However, the patients with PH (group 3) had significantly higher (P < 0.01) blood levels of NO-related compounds (117.3 +/- 14.7 mumol/L) than the patients without PH (groups 1 and 2, 23.9 +/- 3.2 and 38.4 +/- 4.8 mumol/L, respectively). In addition, pulmonary artery resistance (Rp) values of less than 6 Wood U/m2 were directly correlated with levels of NO-related compounds, whereas Rp values greater than 6 Wood U/m2 were inversely correlated with blood levels of NO-related compounds. CONCLUSION: The present results suggest that the hemodynamic status of the pulmonary circulation in CHD affects, at least partly, blood levels of NO-related compounds.     

先天性心脏病肺高压肺血管功能与结构的改变

目的：通过对先天性心脏病肺动脉高压(肺高压)患者血浆中血栓素B2/6-酮-前列环素F1a (TXB2/6-K-PGF1a),Von Willebrand因子(VWF：Ag),组织纤溶酶原激活物(tPA)测定及形态学改变(光、电镜改变)的研究,结合血液动力学,以探讨肺高压的发生机制。方法：分别采用放免分析、免疫扩散电泳法、发色底物分析法测定TXB2/6-K-PGF1a,VWF：Ag,tPA及对肺活检组织行光、电镜检查及VWF：Ag免疫过氧化酶染色。根据肺血管阻力(PVR)将病例分为3组(Ⅰ组PVR≤3.5 wood's单位;Ⅱ组PVR 3.5～5 wood's单位;Ⅲ组PVR>5 wood's)。结果：①肺高压组中TXB2/6-K-PGF1a,VWF：Ag明显上升,不同程度肺高压组中存在显著性差异(P<0.05),且血浆中VWF：Ag与PVR,肺小动脉阻力(PAR)成直线正相关(r=0.89,0.82),而tPA无明显改变。②随着肺高压的发展变化,肺血管内皮内的粗面内质网,微管微丝增生活跃,内膜下有大量弹力蛋白,且有纤维组织明显增生;VWF：Ag免疫过氧化酶染色随病理改变的严重而加深,同时肺血管病理改变的严重程度与临床生理检测到的肺高压的严重程度是一致的。结论：肺血管功能、结构改变可能是先天性心脏病肺高压发生的关键因素,本研究为药物干预性防治肺高压的发生提供了一定的理论依据。     

Serum Level of Soluble Intercellular Adhesion Molecule-1 Correlates with Pulmonary Arterial Pressure in Children with Congenital Heart Disease

Background  Endothelial activation and vascular inflammation are thought to be the mechanisms of pulmonary hypertension. Increased expression of the intercellular adhesion molecule (ICAM-1) and raised serum level of its soluble form (sICAM-1) are found in various conditions associated with endothelial activation. Methods  Serum samples from 31 children (14 boys and 17 girls; age, 4.9 ± 4.6 years) with congenital heart disease (CHD) collected at the time of cardiac catheterization were analyzed for sICAM-1 level. Uni- and multivariable stepwise linear regression analyses were performed for the following variables against the sICAM-1 level: age, hemoglobin, serum creatinine, systemic arterial pressure (SAP), pulmonary arterial pressure (PAP), pulmonary blood flow (Qp) and resistance (Rp), systemic blood flow (Qs) and resistance (Rs), Qp/Qs, Rp/Rs, and pulmonary and systemic oxygen saturation. Results   The sICAM-1 levels in children who had CHD with and without pulmonary hypertension were 411 ± 110 and 344 ± 81 ng/ml, respectively (p = 0.11). In the univariable models, age, serum creatinine, systolic PAP, mean PAP, diastolic PAP, Rp, and Rp/Rs were significantly correlated with sICAM-1 level. In the multiple stepwise regression model, only mean PAP remained as an independent predictor of sICAM-1 level (r = 0.55; p = 0.002). Conclusion  Children with CHD and pulmonary hypertension had a trend toward elevated sICAM-1 compared with CHD children who had no pulmonary hypertension. A linear correlation was found between mean pulmonary arterial pressure and sICAM-1 level.     

复杂性先天性心脏病的介入治疗

目的探讨先天性心脏病(简称先心病)介入治疗在复杂性先心病中的应用.方法应用Rashkind球囊导管对59例复杂性先心病患儿行球囊房隔造口术(BAS);对2例右室发育不良综合征患儿进行静态球囊房隔扩张造口术;对1例在大动脉转位术后出现肺动脉吻合口狭窄的完全性大动脉转位(TGA)的患儿,采用球囊扩张导管进行扩张;对15例法洛四联症(TOF)患儿进行经皮球囊肺动脉瓣成形术(PBPV)、球囊血管成形术;对18例合并主动脉至肺动脉侧支血管的患儿以及5例B-T分流术的患儿在外科根治术前采用弹簧圈进行侧支血管和分流管道的堵塞术;对1例Fontan手术后的先心病患儿采用Amplatzer房间隔缺损(简称房缺)堵塞装置进行窗孔堵塞术.结果46例TGA患儿BAS后动脉血氧饱和度(SaO2)由0.57±0.17上升至0.76±0.13(t=14.58, P<0.01),左右心房压差﹤2 mmHg(1 mmHg=0.133 kPa),术后房缺5～20 mm;10例肺动脉闭锁伴室间隔完整的患儿BAS后SaO2变化不大(t=1.57, P﹥0.05),左右心房压差﹤2 mmHg;TOF患儿经PBPV及球囊血管成形术后SaO2平均上升15%,肺动脉瓣狭窄解除;18例主动脉至肺动脉侧支血管堵塞术,14例效果良好被完全堵塞;5例B-T分流管道堵塞术,全部封堵成功;1例Fontan手术后窗孔堵塞术,获完全封堵.结论复杂性先心病应用介入治疗和外科手术相配合,可获得更好的疗效.     

Pulmonary vascular response to digoxin in newborn lambs

The effects of digoxin on pulmonary vascular resistance (PVR) were evaluated in normoxic (N) and hypoxic (H) newborn lambs with normal and elevated PVR, respectively. Lambs were anesthetized and instrumented to enable continuous measurement of mean pulmonary arterial pressure (PPA), mean left atrial pressure (PLA), mean pulmonary blood flow (Qp), and mean aortic pressure (PAO). Digoxin (10-20 micrograms/kg) was injected via central venous catheters in 11 N lambs and 4 H lambs. Under N conditions, baseline PVR was equal to 0.12 mm Hg/ml/min/kg, PPA was 33 mm Hg, PLA was 6 mm Hg, Qp was 235 ml/min/kg, and PAO was 69 mm Hg. Following digoxin, mean PVR increased by 24% (P less than 0.001) and PPA increased by 23% (P less than 0.001) for an average duration of 199 sec while QP increased by 5% (P less than 0.02) and PLA was constant suggesting a direct vasoconstrictive effect. Under H conditions, baseline PVR was equal to 0.26 mm Hg/ml/min/kg, PPA was 58 mm Hg, PLA was 4 mm Hg, Qp was 208 ml/min/kg, and PAo was 65 mm Hg. Following digoxin, mean PVR, Qp, PLA, and PAo did not change appreciably although PPA had a uniform increase of 5% (P less than 0.001). The blunted response may suggest that either the pulmonary vascular bed was maximally constricted or that digoxin and hypoxia share a common mechanism. In conclusion, digoxin has a direct pulmonary vasoconstrictor action in newborn lambs. Because of its short duration, this action probably should not alter the clinical use of this drug in newborn humans.     

Thermodilution Qp/Qs: An indicator dilution method

The pulmonary-to-systemic blood flow ratio (Qp/Qs) is critical in the appraisal of the need for surgery in patients with left-to-right shunts. Because of the drawbacks present with conventional Fick, indicator dilution, and radionuclide techniques of Qp/Qs measurement, we sought to determine whether an extension of thermodilution technology could accurately predict Qp/Qs. We studied 30 children with clinically suspected or postoperative atrial or ventricular septal defects. The thermodilution temperature curves from the pulmonary artery were printed on a strip chart recorder after right atrial injection of iced solution. Gamma variate curve fitting and area analysis were used to determine Qp/Qs. The correlation between Fick and thermodilution Qp/Qs values was excellent (r = 0.95). The thermodilution technique was rapid, and did not require either arterial entry, radiation after venous catheter placement, or multiple sampling.     

Effects of antenatal glucocorticoids on circulatory adaptation at birth in the ovine fetus

OBJECTIVE: Adaptation to extra-uterine life requires dramatic increase in pulmonary blood flow. Mechanisms that induce pulmonary vasodilatation at birth are incompletely understood but include alveolar ventilation, increase in PaO2, and production of vasoactive mediators. We hypothesized that antenatal glucocorticoids (GC) increase pulmonary vasodilatation to birth-related stimuli. STUDY DESIGN: To test this hypothesis, we studied the pulmonary hemodynamic response at birth to mechanical ventilation with low (<10%) and then with high (100%) FiO2 in chronically prepared late-gestation fetal lambs treated or not by antenatal maternal steroids. RESULTS: Basal mean aortic and pulmonary artery pressure (PAP), left pulmonary blood flow, pulmonary vascular resistance (PVR), and blood gas were similar between control and dexamethasone-treated animals (GC group). During mechanical ventilation with low FiO2, mean PVR decreased by 40% in the control group (from 0.44 +/- 0.01 to 0.25 +/- 0.01 mm Hg/ml/min) and by 60% in the GC group (from 0.44 +/- 0.02 to 0.19 +/- 0.02 mm Hg/ml/min) (p < 0.01). When subsequently ventilated with 100% O2, there was no difference in PVR decrease between groups (0.15 +/- 0.02 mm Hg/ml/min in the GC group vs. 0.14 +/- 0.01 mm Hg/ml/min in the control group). CONCLUSION: Antenatal GC enhance pulmonary vasodilatation induced by alveolar ventilation at birth but do not alter the pulmonary vascular response to O2. We speculate that antenatal steroids exposure improve adaptation at birth through acceleration of both parenchymal and vascular lung maturation.     

Early Outcomes After Extracardiac Conduit Fontan Operation Without Cardiopulmonary Bypass

Cardiopulmonary bypass is associated with a systemic inflammatory response. The authors hypothesized that avoiding cardiopulmonary bypass would lead to improved postoperative outcomes for patients undergoing the extracardiac Fontan operation, the final stage in surgical palliation of univentricular congenital heart defects. A review of the Children's Heart Center Database showed a total of 73 patients who underwent an initial Fontan operation at Lucile Packard Children's Hospital at Stanford between 1 November 2001 and 1 November 2006. These patients were divided into two groups: those who underwent cardiopulmonary bypass (n?=?26) and those who avoided cardiopulmonary bypass (n?=?47). Preoperative demographics, hemodynamics, and early postoperative outcomes were analyzed. The two groups had comparable preoperative demographic characteristics and hemodynamics except that the average weight of the off-bypass group was greater (17.9?±?9.1 vs 14.2?±?2.7?kg; P?=?0.01). Intraoperatively, the off-bypass group trended toward a lower rate of Fontan fenestration (4.3 vs 19.2%; P?=?0.09), had lower common atrial pressures (4.6?±?1.4 vs 5.5?±?1.5?mmHg; P?=?0.05), and Fontan pressures (11.9?±?2.1 vs 14.2?±?2.4?mmHg; P?≤?0.01), and required less blood product (59.1?±?37.6 vs 91.9?±?49.4?ml/kg; P?≤?0.01). Postoperatively, there were no significant differences in hemodynamic parameters, postoperative colloid requirements, duration of mechanical ventilation, volume or duration of pleural drainage, or duration of cardiovascular intensive care unit or hospital stay. Avoiding cardiopulmonary bypass influenced intraoperative hemodynamics and the incidence of fenestration but did not have a significant impact on the early postoperative outcomes of children undergoing the Fontan procedure.     

Radionuclide angiographic and echocardiographic quantitation of left-to-right shunts in children with ventricular septal defect

Summary Pulmonary to systemic blood flow ratios (Qp:Qs) were estimated in 16 children with ventricular septal defects using simultaneous echocardiography and radionuclide angiography, and compared to Qp:Qs measured at cardiac catheterization by the Fick principle method (Fick). When ratios of echographic left atrial dimensions (LAD) to body surface area (LAD/M²), body length (LAD/ht), and aortic root diameter (LAD/Ao) were compared to the Qp:Qs determined by Fick, the correlation coefficients were r=0.70 for LAD/M², r=0.66 for LAD/ht, and r=0.54 for LAD/Ao. The correlation coefficients between Qp:Qs by Fick, and left ventricular dimensions/M² and fractional shortening of the left ventricle were not significant. The correlation coefficients between Qp:Qs and the ratios estimated by gamma-variate and area-ratio analysis of radioisotope pulmonary dilution curves were r=0.92 and r=0.84, respectively. Thus, radionuclide angiography provided more accurate quantitation of left to right shunting through a ventricular septal defect than echocardiography. However, difficulty in obtaining adequate bolus injections of the radioisotope may result in technical failures whereas echocardiographic measurement is possible in almost all pediatric patients. Finally, the gamma-variate method cannot accurately quantitate shunt ratios greater than 3.5 to 1.Supported in part by USPHS Grant Nos. 1-T32HL07417-01 and 5-T01HL05728-09 and American Heart Association Southwest Ohio Chapter