Mechanisms of adrenomedullin-induced increase of pulmonary blood flow in fetal sheep

Mechanisms of adrenomedullin-induced increases in fetal pulmonary blood flow were examined in 19 near-term fetal sheep using four key blocker drugs: nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine), calcitonin gene-related peptide (CGRP) receptor blocker, ATP-dependent potassium (K(ATP)) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin). Catheters were inserted into the left pulmonary artery and superior vena cava to administer drugs and into the main pulmonary and carotid arteries to measure pressures and heart rate. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow continuously. Adrenomedullin (mean 1.06 microg/kg) was injected into the left pulmonary artery before and after infusion of N(omega)-nitro-L-arginine (mean 96.5 mg/kg, n = 6), glibenclamide (mean 11.8 mg/kg, n = 6), CGRP receptor blocker (mean 312.0 microg/kg, n = 6), and indomethacin (mean 1.7 mg/kg, n = 8). Blockade was confirmed by appropriate agonist injection. The adrenomedullin-induced response in left pulmonary artery blood flow was inhibited by N(omega)-nitro-L-arginine (inhibition rate 99%) and significantly attenuated by glibenclamide (inhibition rate 44%); however, no significant changes were found with CGRP receptor blocker or indomethacin (inhibition rate 0 and 17%, respectively). The responses of the main pulmonary and carotid arterial pressures were similarly affected by those blockers. Our data suggest that in the fetal pulmonary circulation, the adrenomedullin-induced increase in pulmonary blood flow depends largely on nitric oxide release and partly on K(ATP) channel activation, and does not involve the CGRP receptor or a cyclooxygenase-mediated mechanism.     

Thromboxane is not responsible for the high pulmonary vascular resistance in fetal lambs

The factors responsible for the high pulmonary vascular resistance in the fetus are not well known. Thromboxane (TX) A2 is a potent pulmonary vasoconstrictor. To determine whether TXA2 may play a role in fetal pulmonary vasoconstriction, we infused the specific TX synthetase inhibitor U63,557A into eight chronically instrumented fetal lambs (134-137 days gestational age, full term 145 days) and measured pulmonary blood flow, pulmonary and systemic arterial pressure, and heart rate. U63,557A (3 mg/kg as a bolus then 3 micrograms/kg/min for 120 min infused in the main pulmonary artery) did not change pulmonary blood flow, pulmonary mean arterial pressure, and pulmonary vascular resistance during the infusion and during 2 h following the end of the infusion. During the infusion, TXB2 arterial plasma concentrations decreased from 106.1 +/- 17.5 to 8.7 +/- 2.9 pg/ml. In three of the fetal lambs, immediately after the 2-h infusion of U63,557A, we infused the leukotriene end-organ antagonist FPL 57231 into the main pulmonary artery (1 mg/kg/min for 60 min). TXA2 synthesis inhibition did not prevent the pulmonary vasodilation induced by FPL 57231. Pulmonary blood flow increased from 64.8 +/- 24.4 to 669.5 +/- 65.6 ml/min/100 g lung tissue during the FPL 57231 infusion. We conclude that TXA2 does not play a role in the maintenance of elevated fetal pulmonary vascular tone, either directly or as a mediator of leukotriene action.     

Doppler echocardiographic assessment of pulmonary blood flow in healthy newborns

The aim of this study was to determine interobserver variation in Doppler assessment of mean left pulmonary arterial flow velocity, and its normal values during the first 24 h of life. The interobserver variation was determined by a Bland and Altman analysis of the values of mean velocity measured in 21 newborns by 2 observers. Then, normal values of mean velocity were measured in 15 newborns at 5,10 and 15 min of life in the delivery room, and in 14 other newborns at 1, 2, 6, 12 and 24 h of life in the nursery unit. The interobserver variation was found to be acceptable. Mean velocity had a few variations within the first 24 h, but remained consistently above 20 cm s^-1. In conclusion, mean velocity values below 20 cm^-1 suggest low pulmonary blood flow.     

Effect of lung hypoplasia on birth-related changes in the pulmonary circulation in sheep

Lung hypoplasia (LH) is a serious cause of neonatal compromise, but little is known of its functional effects on the pulmonary circulation. Our aim was to characterize birth-related changes in the pulmonary circulation of newborn lambs with LH and to compare them with alterations in respiratory function. LH was induced in six ovine fetuses by the creation of a tracheo-amniotic shunt as well as amniotic fluid drainage starting at 105.6+/-1.5 (mean+/-SEM) days of gestation (term approximately 147 d). At 139.9+/-0.3 d, fetuses were exteriorized under anesthesia to implant vascular catheters and an ultrasonic flow probe around the left pulmonary artery. The lambs then were delivered and ventilated for 2 h, during which systemic and pulmonary artery pressures, left pulmonary blood flow, and measures of respiratory function were recorded. At autopsy, lungs were weighed and volume was measured at 20 cm H2O. In LH lambs, lung weight was 25% lower and respiratory system compliance was 30% lower than in controls. Mean pulmonary blood flow in LH lambs was 42% lower and pulmonary vascular resistance was 138% higher than in controls. Morphometry showed that volume density of pulmonary arteries in LH was 30% lower than in controls. We conclude that, in this LH model, changes in ventilatory indices were proportional to the change in lung size, whereas changes in the pulmonary circulation were greater than the change in lung size and were associated with reduced density of pulmonary arteries. LH severely impairs normal adaptation of the pulmonary circulation in the perinatal period.     

Prolonged infusions of estradiol dilate the ovine fetal pulmonary circulation

Factors mediating both the rapid and sustained fall in pulmonary vascular resistance (PVR) at birth are incompletely understood. Acute or prolonged estrogen treatment causes vasodilation of several vascular beds in adults. Although fetal estrogen levels rise in late gestation, their effects in the fetal pulmonary circulation have not been studied. To determine whether estrogens can cause pulmonary vasodilation in the fetus, we infused 17beta-estradiol (E2) into the left pulmonary artery (LPA) of chronically catheterized fetal lambs, measured pulmonary artery pressure and LPA blood flow, and calculated PVR. Brief E2 administration (1-, 10-, and 100-microg doses) did not change baseline pulmonary hemodynamics and failed to enhance endothelium-dependent vasodilation as assessed by the dilator response to acetylcholine. However, prolonged E2 infusion (2- 8 d) caused a 2.6-fold increase in pulmonary blood flow (73+/-6 versus 188+/-44 mL/min, baseline versus E2 treatment, p<0.05), and the response was sustained for at least several hours. Treatment with the nitric oxide synthase inhibitor nitro-L-arginine (L-NA) reversed the E2-induced fall in PVR (0.15+/-0.05 versus 0.51+/-0.15 mm Hg/mL/min; before versus after L-NA, p<0.05). Endothelial nitric oxide synthase expression and endothelin-1 content were not different in E2-responders and controls, suggesting that altered expression of these mediators did not account for the increased flow. We conclude that prolonged E2 infusion causes an unusual pattern of vasodilation in the ovine fetal lung. On the basis of these observations of exogenous E2 treatment, we speculate that endogenous E2 enhances pulmonary vasodilation at birth.     

Influence of fetal breathing movements on pulmonary hemodynamics in fetal sheep

During fetal development, pulmonary vascular resistance (PVR) is high, and, as a result, blood flow through the fetal lungs is low. Although PVR markedly decreases at the time of birth, the factors that regulate pulmonary blood flow (PBF) and PVR before and immediately after birth are not clear. Our aim was to examine the relationship between episodes of fetal breathing movements (FBM) and pulmonary hemodynamics during late gestation to further understand the relationship among lung luminal volume, phasic changes in intrapulmonary pressure, and PVR before birth. In chronically catheterized fetal sheep (120-128 d gestation; n = 5; term approximately 147 d), PBF and PVR were measured during periods of FBM and apnea. Episodes of FBM were divided into periods of accentuated (amplitude of >3.5 mm Hg change in tracheal pressure) and nonaccentuated periods of FBM. During accentuated episodes of FBM, mean PBF was increased to 159.5 +/- 23.4% (p < 0.0025) of the preceding apneic period and was associated with a 19.1 +/- 5.2% reduction in PVR. In addition, during accentuated episodes of FBM, the retrograde flow of blood through the left pulmonary artery was reduced to 90.1 +/- 1.0% of the preceding apneic period, which most likely contributed to the increase in mean PBF at this time. Although a change in PBF and PVR could not be detected during nonaccentuated FBM, compared with the preceding apneic period, PBF was linearly and positively correlated with the amplitude (change in pressure) of FBM. We conclude that PVR is decreased and PBF is increased during accentuated episodes of FBM, possibly as a result of phasic reductions in intrapulmonary pressures.     

Inhaled nitric oxide improves oxygenation in very premature infants with low pulmonary blood flow

AIM: Inhaled nitric oxide (iNO) is used to reduce right-to-left extrapulmonary shunting by decreasing pulmonary vascular resistance in term or near-term infants. The objectives of this study were to determine, first, the pulmonary blood flow status of very preterm infants with hypoxaemic respiratory failure, then the response of oxygenation to iNO therapy according to pulmonary blood flow (PBF) and, finally, to verify the lack of adverse side effects of iNO on the ductus arteriosus. METHODS: Infants below 32 wk gestational age (GA) with hypoxic respiratory failure and aAO2 < 0.22 were randomized as the control or iNO group. PBF was evaluated by pulsed Doppler measurement of mean pulmonary blood flow velocity (MPBFV) in the left pulmonary artery. Low PBF (LPBF) was defined as MPBFV < 0.2 m/s. RESULTS: Seventy infants of 23 to 31 wk GA with hypoxic respiratory failure were randomized either to receive or not to receive 5 ppm iNO in addition to optimal care. Twenty-eight infants were diagnosed with LPBF (11/35 in iNO vs 17/35 in the control groups). Thirty minutes after receiving iNO the number of LPBF infants dropped to 8/35. In the iNO group, aAO2 increased significantly from 0.14 +/- 0.05 to 0.24 +/- 0.08 after iNO, but only in the LPBF infants (mean +/- SD; p = 0.027). CONCLUSION: In infants below 32 wk GA with hypoxic respiratory failure, Doppler echocardiographic assessment of LPBF seems to be able to determine which patients are likely to benefit from iNO therapy on systemic oxygenation.     

The effect of increased pulmonary blood flow on the pulmonary vascular bed in pigs.

Increased pulmonary blood flow was produced in 1-month-old piglets by means of left pneumonectomy, arteriovenous fistulas in the neck, and a combination of both. Physiologic and histologic studies of the pulmonary vascular bed were done 1-9 months after operation. A progressive, moderate increase in pulmonary artery (PA) pressure was observed, especially between 1 and 6 months after surgery. This was flow related, i.e., the group with the highest flow (pneumonectomy plus fistula) was found to have the most prominent increase in pressure. Mean Pa pressure at 6 months was 28.7 +/- 0.07 mm Hg in this group, vs 24.4 +/- 0.48 mm Hg in the group with pneumonectomy alone and 17.2 +/- 0.48 mm Hg in controls (P less than 0.01). The pressure response to hypoxia in pigs with high pulmonary blood flow was not different from that found in control animals. Histologic studies revealed that small arteries and arterioles of pigs with high pulmonary blood flow had a decreased relative wall thickness because of dilation up to 6 months follow-up. This was flow related, the group with the highest flow having the lowest wall thickness to vessel diameter ratio; relative wall thickness (in percentage of the vessel diameter ) at 6 months was 6.1 +/- 0.44% in pigs with with pneumonectomy plus fistula, vs 9.6 +/- 0.40% in the group with pneumonectomy alone and 11.2 +/- 0.61% in controls (P less than 0.01). In the group with the highest flow, thick walled arterioles appeared at 9 months follow-up, scattered among dilated ones; between 6 and 9 months after operation, ranging from 6.1 +/- 0.44% to 11.3 +/- 0.73% (P less than 0.01). In five animals with high flow, the right PA (main branch) showed patchy intimal thickening, small cystic spaces filled with mucopolysaccharides in the media, and muscular hypertrophy.     

Persistent pulmonary hypertension in premature neonates with severe respiratory distress syndrome.

Cardiac catheterization studies have demonstrated that Doppler-derived flow velocities in the ductal flow jet and the left pulmonary artery accurately predict the aortopulmonary pressure difference and left-to-right shunt size in newborns. To assess the presence of persistent pulmonary hypertension in premature newborns with various degrees of respiratory distress syndrome (RDS) severity, we estimated pulmonary artery pressure from the aortopulmonary pressure difference and pulmonary blood flow from the left pulmonary artery flow velocity with color-flow-directed, pulsed Doppler echocardiography. Seventy-nine premature neonates were divided into three groups--no or mild RDS (n = 27), severe RDS (n = 38), and fatal RDS (n = 14)--and compared with a group of healthy term neonates (n = 34). In premature and term neonates with no/mild RDS the mean +/- SEM aortopulmonary pressure difference increased from 7.3 +/- 0.4 and 6.6 +/- 0.5 mm Hg to 22.8 +/- 1.4 and 21.4 +/- 1.1 mm Hg over the first 24 hours (P < .001). The mean aortopulmonary pressure difference was 0.9 +/- 0.3 mm Hg during the first 72 hours in neonates with fatal RDS, but increased from 1.5 +/- 0.3 mm Hg at 4 hours to 7.4 +/- 0.6 at 24 hours and 21.5 +/- 0.7 mm Hg at 72 hours of age in neonates with severe RDS. Left pulmonary artery velocity time integrals were 18.3 +/- 0.5 cm in premature and 18.8 +/- 0.5 cm in term neonates with no/mild RDS at 12 hours vs 11.2 +/- 0.4 cm in neonates with severe and 9.9 +/- 0.5 cm in neonates with fatal RDS (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Recurrence of hepatic artery thrombosis following acute tacrolimus overdose in pediatric liver transplant recipient

Acute overdose of tacrolimus appears to cause no or minimal adverse clinical consequences. We encountered a pediatric case who underwent liver transplantation associated with hepatic artery thrombosis (HAT), which recurred following acute tacrolimus overdose. A 10-month-old girl underwent living-related liver transplantation because of biliary atresia. To reconstruct the hepatic artery, the right gastroepiploic artery of the donor was interposed between the right hepatic artery of the recipient (2.5 mm in diameter) and the left hepatic graft artery (1 mm in diameter) under microscopy. On postoperative day 4, Doppler ultrasonography showed a remarkable reduction in hepatic arterial flow, which was consistent with HAT. The patient underwent immediate hepatic arteriography and balloon angioplasty. The stenotic sites were dilated by the procedure. Tacrolimus was infused intravenously after transplantation and the infusion rate was adjusted to achieve a target concentration of 18-22 ng/mL, which remained stable until the morning of day 6. An unexpectedly high blood concentration of tacrolimus (57.4 ng/mL) was detected at 6:00 PM on day 6, and tacrolimus was discontinued at 9:00 PM; however, the tacrolimus level reached 119.5 ng/mL at 0:00 h on day 7. While the concentration decreased to 55.2 ng/mL on the morning of day 7, the hepatic arterial flow could not be observed by Doppler ultrasonography. Emergent hepatic arteriography showed stenosis of the artery at the proximal site of the anastomosis. Balloon angioplasty was again performed and the stenotic site was successfully dilated. High level of tacrolimus exposure to the hepatic artery with injured endothelium by preceding angioplasty may have been related to the recurrence of HAT in the present case.     

The effect of an increase in systemic arterial pressure in the newborn with right ventricular hypertension

To evaluate the effect of an elevation in systemic arterial pressure upon pulmonary blood flow and arterial oxygenation during right ventricular hypertension (RVH), we acutely studied 13 1-d-old piglets. Catheters were positioned in the pulmonary artery, both atria, and the aorta for hemodynamic measurements. An electromagnetic probe was positioned in the main pulmonary artery for pulmonary blood flow measurement. Systemic and regional blood flow were measured with the radiolabeled microsphere technique. A balloon-mounted catheter was advanced in the aorta and maintained at the lower thoracic level. After induction of RVH (pulmonary artery banding), a significant decrease in arterial O2 pressure from 54.4 +/- 1.6 to 10.6 +/- 0.4 kPa (p less than 0.01), a 30% reduction in systemic arterial pressure, and a 44% decrease in pulmonary blood flow were observed. During RVH, partial inflation of the aortic balloon to restore the systemic arterial pressure to its initial value led to an increase in arterial O2 pressure to 23.5 +/- 3.1 kPa (p less than 0.01). Full inflation of the balloon further increased the arterial O2 pressure to 32.6 +/- 2.9 kPa (p less than 0.01). Aortic balloon inflation increased pulmonary blood flow in 11 and systemic O2 delivery in nine of the 13 animals. RVH was associated with a significant increase in cerebral and right ventricular myocardial free-wall blood flow and a decrease in renal and bowel blood flow and O2 delivery (p less than 0.01). Aortic balloon inflation during RVH did not change either the cerebral or myocardial free-wall blood flow, but further significantly decreased renal and bowel blood flow and O2 delivery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ductus venosus flow velocity in newborn lambs during increased pulmonary artery pressure

The aim of the present study was to assess with ultrasound the ductus venosus flow velocity in newborn lambs with increasing pulmonary artery pressures and to evaluate whether this is a useful method to detect elevated pulmonary artery pressure. The ductus venosus flow velocity was studied with pulsed-wave Doppler echocardiography in nine newborn lambs < or = 30 h old. The lambs were anesthetized, mechanically ventilated, and instrumented to measure mean airway pressure and pulmonary artery and arterial blood pressures. A vascular occluder was placed around the main pulmonary artery. With mean pressures ranging from 20 to 50 mm Hg in the pulmonary artery, the ductus venosus flow velocity was examined. In seven lambs, the mean portal pressure and central venous pressure were also measured. With a stepwise increase in the pulmonary artery pressure, the minimum ductus venosus flow velocity during atrial systole decreased to a reversed flow, and the duration of this reversed flow component increased. The systolic forward peak flow velocity signal also gradually decreased. No changes were detected in the mean central venous or in the portal pressure with increasing pulmonary artery pressure or changes in ductus venosus flow. The flow velocity in the ductus venosus, which is higher than in other precordial veins, shows a reduction and even reversal of the nadir and an increase of the duration of reversed flow during atrial systole as a response to increased pulmonary artery pressure. Thus, Doppler ultrasound of the ductus venosus flow velocity may be a useful noninvasive diagnostic supplement to detect pulmonary hypertension of the newborn.     

Effects of an aorticopulmonary shunt on lung fluid balance in the young lamb

We studied the effects of increased pulmonary blood flow on lung fluid balance in seven chronically instrumented lambs (18 +/- 1 d) with surgically created aorticopulmonary shunts. We measured mean pulmonary arterial and left atrial pressure (LAP), pulmonary blood flow, lung lymph flow, and lymph (CL) and plasma (CP) protein concentration with the shunt closed and opened. With the shunt partially open, a 35% increase in pulmonary blood flow resulted in an increase in pulmonary arterial pressure (15.5 +/- 1 to 19.5 +/- 1 torr) and LAP (2.0 +/- 0.5 to 3.5 +/- 0.5 torr). Lung lymph flow nearly doubled (1.53 +/- 0.28 to 2.83 +/- 0.52 mL/h) whereas the CL decreased (4.1 +/- 0.1 to 3.4 +/- 0.1 g/dL) resulting in a decrease in the CL/CP ratio (0.67 +/- 0.01 to 0.58 +/- 0.01). With the shunt fully open, pulmonary blood flow increased 65% over baseline, pulmonary arterial pressure increased from 16.5 +/- 2.0 to 26.5 +/- 5 torr, and LAP increased from 1.5 +/- 0.5 to 6.5 +/- 2.0 torr. Lung lymph flow increased (1.1 +/- 0.2 to 3.1 +/- 0.2 mL/h) whereas CL (4.1 +/- 0.1 to 3.1 +/- 0.3 g/dL) and CL/CP (0.66 +/- 0.02 to 0.51 +/- 0.05) decreased. All changes were statistically significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Asymmetry of cerebral blood flow velocity in low birth weight infants

BACKGROUND: In premature infants, intraventricular hemorrhage occurs more commonly in the left than the right hemisphere. We have demonstrated previously that cerebral blood flow velocity is lower in the left than the right middle cerebral artery in the first few hours after birth. This may be due to the open ductus arteriosus. OBJECTIVE: To test the hypothesis that blood flow velocity is lower in the left than the right middle cerebral artery only when the ductus arteriosus is open. STUDY DESIGN: Infants born at 25-33 weeks' gestation were enrolled. Middle cerebral artery blood flow velocities and coefficients of variation were measured on the left, followed by the right, on days 1 and 7 of life. Echocardiography identified 67 infants (25-33 weeks, 517-2,371 g) whose ductus arteriosus was open on day 1 and closed on day 7. RESULTS: Systolic (26.4 +/- 7.4 vs. 29.6 +/- 7.2 cm/s), mean (12.4 +/- 4.0 vs. 15.6 +/- 4.6 cm/s) and end-diastolic (5.3 +/- 2.2 vs. 6.8 +/- 2.9 cm/s) blood flow velocities were lower (p < 0.01) and the corresponding coefficients of variation were higher (p < 0.01) on the left on day 1. Neither the absolute Doppler blood flow velocities nor the coefficients of variation differed between the left and right sides on day 7. CONCLUSIONS: Blood flow velocity is lower and more variable in the left compared to the right middle cerebral artery on day 1 of life in premature infants. These differences are not found on day 7. We speculate that this difference is due to the associated ductus arteriosus patency.     

Adaptation of fetal pulmonary blood flow to local infusion of tolazoline

Although tolazoline is the most commonly used drug in the treatment of neonatal pulmonary hypertension, its mode of action and efficacy remain incompletely understood. In order to study the effects of tolazoline on a high resistance pulmonary circulation and to better understand mechanisms that control pulmonary vascular tone and reactivity in the fetus, we infused tolazoline either continuously or as bolus into the left pulmonary artery of 15 chronically instrumented, normoxic fetal lambs during late gestation. The vasodilatory effects of bolus injections of tolazoline (2.5 mg) were inhibited by the prior administration of the histaminergic receptor blockers, cimetidine (56%), diphenhydramine (56%), or both (100%). During the continuous infusion of tolazoline (4.5 mg/h for 9 min), pulmonary blood flow to the left lung increased from 61 +/- 6 ml/min (mean +/- SE; control) to 100 +/- 10 (peak) at 30 min (p less than 0.001). However, following this initial vasodilatation, pulmonary blood flow steadily decreased toward control values by 90 min, despite the continued infusion of tolazoline (p less than 0.001). Although the calcium channel blocker, verapamil, and the alpha-adrenergic blocker, phentolamine, had little effect on fetal pulmonary blood flow when infused alone, both drugs increased the vasodilatory response to tolazoline (p less than 0.001). We conclude that tolazoline effects pulmonary vasodilatation by a histaminergic mechanism and that subsequent refractoriness to the drug is a calcium-dependent process which may be partially mediated by an alpha-adrenergic mechanism.     

Doppler flow profiles in the right and left pulmonary artery in children with congenital heart disease and a bidirectional cavopulmonary shunt

Summary The systolic and diastolic Doppler tracings in the right and left pulmonary artery were analyzed in 10 patients with complex cyanotic congenital heart disease, aged 6 months to 12 years (median 3 years), after employment of a bidirectional cavopulmonary shunt. The postoperative interval ranged from 2 weeks to 1.7 years (median 1.3 years). In children with pulmonary atresia or severe pulmonary stenosis with minimal antegrade pulsatile pulmonary blood flow Doppler echocardiography confirmed a systolic and diastolic bidirectional shunt from the vena cava superior to both pulmonary arteries. In children with pulmonary stenosis, Doppler echocardiography confirmed a systolic shunt only to the right pulmonary artery and a diastolic bidirectional shunt into both pulmonary arteries. As the left pulmonary artery was perfused by the pulsatile transvalvular flow it was difficult to detect a concomitant systolic Glenn-related flow in those patients. Quantitative analysis of the diastolic Doppler tracings revealed a significant difference in the velocity time integral in the right and left pulmonary artery indicating a dominant right lung perfusion in diastole.Deceased     

Morphometric study of the role of pulmonary arterial flow in fetal lung growth in sheep

Pulmonary hypoplasia has been associated with absent or hypoplastic pulmonary artery in four cases in humans. Despite these reports, the effects of decreased pulmonary arterial flow on fetal lung growth have not been adequately studied. This study defines the effects of left pulmonary artery (LPA) ligation on fetal lung growth in sheep by comparing morphometrically determined pulmonary volumes from LPA-ligated, sham-operated, and un-operated control fetuses. LPA ligation (n = 5) or sham operation (n = 4) was performed at 105- to 114-d gestation. lungs were intratracheally fixed for light microscopy. At 112 d (n = 4) and at 140 d (n = 4), unoperated control fetuses were similarly delivered. Absolute pulmonary volumes were then measured using standard stereologic methods. Normal growth of the left lung from 112 to 140 d resulted in significant increases in wet and dry wt, displacement volume, and volumes of future airspace and capillary contents. LPA ligation caused significant decreases in left lung wet and dry wt, displacement volume, and in absolute volumes of fine nonparenchymal, future airspace, parenchymal tissue, and capillary contents compared to sham-operated and 140-d controls. Parenchymal tissue volume was also less than in 112-d controls. In addition, lung wt, displacement volume, and future airspace volume were significantly decreased in sham-operated fetuses compared to 140-d controls. The effects of LPA ligation on bronchial collateral circulation and factors known to affect lung growth (i.e. lung fluid volume) remain to be determined. Clearly, during the canalicular and alveolar stage of fetal lung development, pulmonary arterial flow is necessary for normal lung growth.     

Adenosine triphosphate and adenosine increase the pulmonary blood flow to postnatal levels in fetal lambs.

We investigated the hypothesis that purine nucleotides may mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We studied nine fetal lambs 3 d after placement of intravascular catheters, a flow transducer around the left pulmonary artery, and an inflatable vascular occluder around the ductus arteriosus. The pressure-flow relationship of left lung during a brief occlusion of the ductus arteriosus was studied as an index of pulmonary vascular resistance. We investigated the pulmonary vascular effects of adenosine, ATP, or saline (control) in doses of 0.01-2.50 mumol/kg/min infused into the right atrial line, and measured blood adenosine and ATP levels in samples from the pulmonary artery and left atrium. We also investigated the mechanism of pulmonary vascular effects of adenosine and ATP. Adenosine and ATP caused significant decreases in pulmonary vascular resistance and increases in pulmonary blood flow in doses of 0.08-2.5 mumol/kg/min. The pulmonary blood flow increased to levels seen in postnatal lambs at doses of 1.2 and 2.5 mumol/kg/min of adenosine and ATP. The baseline blood adenosine and ATP levels in fetus were 8 and 70% of levels in postnatal lambs. ATP concentrations increased to postnatal levels and adenosine levels increased to 20% of postnatal levels at infusion rates of 1.2 and 2.5 mumol/kg/min. The pulmonary vasodilation caused by adenosine and ATP was attenuated by 8-phenyltheophylline and cibacron blue, respectively, but not by indomethacin. We conclude that adenosine and ATP are pulmonary vasodilators and increase the fetal pulmonary flow to postnatal levels in doses that increase their blood concentrations to less than or equal to postnatal levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Echocardiographic assessment of early circulatory status in preterm infants with suspected intrauterine infection

OBJECTIVE: To assess early circulatory status in very low birthweight (VLBW) infants with suspected intrauterine infections. PATIENTS: Thirteen VLBW infants who were diagnosed with prenatal infections because of raised serum IgM at birth (infectious group), and 39 infants matched for gestational age and birth weight (control group). METHODS: Echocardiographic assessments were performed consecutively from birth to day 28 in all VLBW infants. Left ventricular output (LVO) and left ventricular stroke volume (LVSV) were measured using Doppler echocardiography. Pulsed Doppler assessment of pulmonary artery pressure (PAP) was performed using the corrected ratio of the pulmonary artery acceleration time to the right ventricular ejection time (AT/RVET(c)). Blood flow in the superior mesenteric artery (SMA) was also evaluated by Doppler ultrasound. RESULTS: Mean LVO and LVSV were both significantly higher in the infectious group than in the control group at 12 hours (LVO; 188 v 154 ml/kg/min) and 72 hours (LVO; 216 v 173 ml/kg/min) of life. Pulsed Doppler assessment of PAP showed that mean AT/RVET(c) values were significantly lower in the infectious group than in the control group at 48 hours, 96 hours, day 14, and day 28. In the analysis of SMA flow velocities, both peak systolic velocities and time averaged velocities had decreased significantly in the infectious group compared with the control group at 24 hours, 36 hours, 96 hours, and day 28. CONCLUSIONS: VLBW infants with suspected prenatal infection showed a unique circulation status, namely high cardiac output, latency of high PAP, and low organ flow.     

肾上腺髓质素在先天性心脏病中的测定及临床意义

目的：肾上腺髓质素(ADM)对心血管疾病有多方面的影响,但其与先天性心脏病关系的研究较少。该实验通过检测不同类型先天性心脏病患儿体内ADM的变化,分析ADM在先天性心脏病病理生理中的作用。方法：筛选住院的48例先天性心脏病患儿,经超声心动图及心导管检查术证实,在心导管检查术中测定血流动力学指数及采血备测,依据血流动力学特征分为高肺血流非肺动脉高压组、高肺血流并肺动脉高压组、紫绀组,平均肺动脉压(mPAP)>20 mmHg为肺动脉高压的标准。选6例川崎病痊愈患儿作为对照组。采用特异性放射免疫法检测血浆ADM的水平。结果：先天性心脏病患儿股静脉中的血浆ADM水平较股动脉明显增高(P<0.05);与对照组相比,高肺血流并肺高压组及紫绀组中的ADM明显增高,均P<0.01;ADM与主动脉平均压(mSAP)、混合静脉血氧饱和度(MVsat)、主动脉血氧饱和度(AOsat)及肺血管阻力(Rp)之间有密切的关系。结论：高肺血流并肺动脉高压和紫绀型先天性心脏病患儿的ADM水平增高,ADM的变化同肺动脉阻力和缺氧有密切关系,推测ADM水平的升高可能有助于减轻肺动脉阻力和改善缺氧。