Sudden cardiac death in hypertrophic cardiomyopathy: risk evaluation

The pathophysiology of the lamb model of congenital diaphragmatic hernia (CDH) involves pulmonary hypoplasia, pulmonary hypertension, and surfactant deficiency. Inhaled nitric oxide (NO) is a highly selective pulmonary vasodilator. The aim of this study was to determine the effects of inhaled NO on pulmonary gas exchange, acid-base balance, and pulmonary pressures in a lamb model of CDH with or without exogenous surfactant therapy. At the gestational age of 78 days (full term, 145 days) 11 lamb fetuses had a diaphragmatic hernia created via a left thoracotomy and then were allowed to continue development in utero. After cesarean section, performed at term, six lambs received exogenous surfactant therapy (50 mg/kg, Infasurf) and five served as controls. All animals were pressure-ventilated for 30 minutes and then received 80 ppm of inhaled NO at an F1O2 of .9 for a 10-minute interval. Compared with the control lambs, the lambs with exogenous surfactant therapy had higher pH (7.17 +/- .06 v 6.96 +/- .07; P < .05), lower PCO2 (73 +/- 8 v 122 +/- 20, p < .05), and higher PO2 (153 +/- 38 v 50 +/- 23; P < .05). In control CDH lambs (without surfactant), inhaled NO did not improve pH, PCO2, or PO2, or decrease pulmonary artery pressure. In CDH lambs given exogenous surfactant, NO decreased pulmonary artery pressures (42 +/- 4 v 53 +/- 5; P < .005) and further improved PCO2 and PO2. NO also made the difference between pulmonary and systemic artery pressures more negative in the surfactant-treated lambs (-15 +/- 4 v -2.3 +/- 2.4; P < .005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin receptor blockade prevents the rise in pulmonary vascular resistance after cardiopulmonary bypass in lambs with increased pulmonary blood flow

BACKGROUND: Children with increased pulmonary blood flow may experience morbidity as the result of increased pulmonary vascular resistance after operations in which cardiopulmonary bypass is used. Plasma levels of endothelin-1, a potent vasoactive substance implicated in pulmonary hypertension, are increased after cardiopulmonary bypass. OBJECTIVES: In a lamb model of increased pulmonary blood flow after in utero placement of an aortopulmonary shunt, we characterized the changes in pulmonary vascular resistance induced by hypothermic cardiopulmonary bypass and investigated the role of endothelin-1 and endothelin-A receptor activation in postbypass pulmonary hypertension. METHODS: In eleven 1-month-old lambs, the shunt was closed, and vascular pressures and blood flows were monitored. An infusion of a selective endothelin-A receptor blocker (PD 156707; 1.0 mg/kg/h) or drug vehicle (saline solution) was then begun 30 minutes before cardiopulmonary bypass and continued for 4 hours after bypass. The hemodynamic variables were monitored, and plasma endothelin-1 concentrations were determined before, during, and for 6 hours after cardiopulmonary bypass. RESULTS: After 90 minutes of hypothermic cardiopulmonary bypass, both pulmonary arterial pressure and pulmonary vascular resistance increased significantly in saline-treated lambs during the 6-hour study period (P <.05). In lambs pretreated with PD 156707, pulmonary arterial pressure and pulmonary vascular resistance decreased (P <. 05). After bypass, plasma endothelin-1 concentrations increased in all lambs; there was a positive correlation between postbypass pulmonary vascular resistance and plasma endothelin-1 concentrations (P <.05). CONCLUSIONS: This study suggests that endothelin-A receptor-induced pulmonary vasoconstriction mediates, in part, the rise in pulmonary vascular resistance after cardiopulmonary bypass. Endothelin-A receptor antagonists may decrease morbidity in children at risk for postbypass pulmonary hypertension. This potential therapy warrants further investigation.     

Contractile properties of intralobar pulmonary arteries and veins in the fetal lamb model of congenital diaphragmatic hernia

BACKGROUND/PURPOSE: Pulmonary hypertension plays a significant role in the pathophysiology of congenital diaphragmatic hernia (CDH). Although there has been an intensive research effort directed at mediators that may cause pulmonary vasoconstriction, no single agent has been identified. The authors hypothesize that there may be an alteration in the cGMP-nitric oxide (NO) pathway of vasodilatation contributing to the pulmonary hypertension observed in CDH. The purpose of these studies is to begin to elucidate vasoactive properties of pulmonary vessels with particular attention to the cGMP-NO pathway of vasodilatation in fetal lambs with CDH. METHODS: Fourth-generation pulmonary arteries and pulmonary veins were dissected from both right and left lungs of eight, 139-day gestational fetuses with surgically created CDH. Vessels were studied with standard isolated tissue bath techniques. Experiments examined basal release of NO in endothelium-intact PVs and PAs of both right and left lungs by measuring the contractile force of vessels constricted with norepinephrine (NE) in the presence and absence of the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NA). Concentration-response curves to the vasodilating agents zaprinast and A23187 were also obtained in vessels contracted by NE. RESULTS: Left and right pulmonary artery responses to NE are enhanced over those of historic controls. Pretreatment of left pulmonary arteries with L-NA enhances the vasoconstrictor response to NE, whereas right PAs show no increased response. Relaxation responses to A23187 and zaprinast, in both left and right pulmonary arteries were not different from control lambs. Relaxation responses of both left and right pulmonary veins to A23187 and zaprinast are blunted compared with controls. This blunting is significantly more in left pulmonary veins than right. Further, right but not left pulmonary veins display enhanced vasoconstrictive response to NE after L-NA pretreatment. CONCLUSIONS: The NO-cGMP pathway of vasodilatation is abnormal in the near term, fetal lamb with CDH. These abnormalities were most apparent in pulmonary veins and may reflect abnormal NOS activity or content between left and right lungs of the fetal lamb with CDH. Pulmonary arteries from CDH lambs have basal and stimulated NO release equal to that of historic controls but appear to be hypersensitive to exogenous vasoconstrictors.     

Cardio-pulmonary function during acute unilateral occlusion of the pulmonary artery in broilers fed diets containing normal or high levels of arginine-HCl

Cardio-pulmonary function was measured in male broilers reared on diets formulated to contain 1.5% arginine (NORMAL group) or 2.5% arginine (ARGININE group). A snare placed around the right pulmonary artery permitted acute shunting of the entire cardiac output (CO) through the left pulmonary artery, resulting in sustained increases in blood flow (BF) through the left lung in both groups. The unilateral increase in BF was accompanied by sustained increases in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in the NORMAL group. However, following initial transient increases in PAP and PVR in the ARGININE group, subsequent pulmonary vasodilation gradually reduced PVR, and thus PAP, in spite of the ongoing elevation of BF through the left lung. The capacity of the pulmonary vasculature in the ARGININE group to accommodate an increased BF at a normal PAP accounts for the previously reported lower incidence of pulmonary hypertension syndrome (PHS, ascites) in cold-stressed broilers fed supplemental dietary arginine. Hypoxemia and respiratory acidosis ensued rapidly in both groups after tightening the pulmonary artery snare, in spite of a compensatory increase in the respiratory rate. The gradual return of PVR and PAP to presnare levels in the ARGININE group did not eliminate the concurrent ventilation-perfusion mismatch caused by the increased rate of BF through the left lung. Tightening the pulmonary artery snare caused mean systemic arterial pressure (MAP) to drop from control levels of approximately 98 mm Hg to sustained hypotensive levels of approximately 65 mm Hg in both groups. This systemic hypotension was caused by decreases in CO and total peripheral resistance (TPR). The reduction in CO were caused by reduction in stroke volume (SV) rather than heart rate (HR), suggesting that acutely tightening the pulmonary artery snare increased PVR sufficiently to impede left ventricular filling. Accordingly, the maximum increment in PAP attainable by the right ventricle during acute increases in PVR apparently was inadequate to propel the entire CO through the pulmonary vasculature, setting the stage for the congestive right-sided pooling of blood routinely associated with PHS in broilers.     

Liquid assisted ventilation: an alternative ventilatory strategy for acute meconium aspiration injury

Evidence of surfactant inactivation by meconium has led to the use of exogenous surfactant therapy in the management of meconium aspiration syndrome (MAS). Liquid assisted ventilation has been shown to improve the cardiopulmonary function in lungs with high surface tension. We compared exogenous surfactant therapy with liquid assisted ventilation in the management of experimental acute meconium aspiration injury. Thirty-two newborn lambs were ventilated at peak inspiratory pressures of 13-16 cm H2O, positive end expiratory pressure of 3-4 cm H2O, fractional inspired oxygen concentration (FiO2) of 1.0, and a respiratory frequency range between 30 and 35 breaths/min. Baseline arterial blood gases, pulmonary function, and arterial blood pressure measurements were taken. All lambs were given 2-3 ml/kg of an unfiltered 25% meconium solution. Lambs were then randomized into either gas-ventilated meconium control, or one of three treatment groups: 1) surfactant; 2) partial liquid ventilation (PLV); or 3) total liquid ventilation (TLV) for 4 hours after meconium injury. All treated groups demonstrated a significant increase in arterial oxygenation (P < 0.05); surfactant and PLV-treated lambs demonstrated significantly decreased arterial PCO2 (P < 0.05). Compliance in all groups increased compared with injury values; compliance of the TLV group increased more than in all other treatment groups (P < 0.05). In addition, lung histology of the TLV group demonstrated clear, intact alveolar epithelium and homogeneously expanded alveoli, while no such improvement was evident in the other groups. These data suggest roles for both exogenous surfactant therapy and liquid assisted ventilation techniques in the management of MAS.     

High-frequency partial liquid ventilation in respiratory distress syndrome: hemodynamics and gas exchange

Partial liquid ventilation using conventional ventilatory schemes improves lung function in animal models of respiratory failure. We examined the feasibility of high-frequency partial liquid ventilation in the preterm lamb with respiratory distress syndrome and evaluated its effect on pulmonary and systemic hemodynamics. Seventeen lambs were studied in three groups: high-frequency gas ventilation (Gas group), high-frequency partial liquid ventilation (Liquid group), and high-frequency partial liquid ventilation with hypoxia-hypercarbia (Liquid-Hypoxia group). High-frequency partial liquid ventilation increased oxygenation compared with high-frequency gas ventilation over 5 h (arterial oxygen tension 253 +/- 21.3 vs. 17 +/- 1.8 Torr; P < 0.001). Pulmonary vascular resistance decreased 78% (P < 0.001), pulmonary blood flow increased fivefold (P < 0.001), and aortic pressure was maintained (P < 0.01) in the Liquid group, in contrast to progressive hypoxemia, hypercarbia, and shock in the Gas group. Central venous pressure did not change. The Liquid-Hypoxia group was similar to the Gas group. We conclude that high-frequency partial liquid ventilation improves gas exchange and stabilizes pulmonary and systemic hemodynamics compared with high-frequency gas ventilation. The stabilization appears to be due in large part to improvement in gas exchange.     

Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs

OBJECTIVE: We hypothesized that fetal betamethasone exposure for < 24 hours would improve postnatal lung function in preterm lambs. STUDY DESIGN: Singleton fetal sheep were randomized to receive by ultrasonographically guided fetal injections of 0.5 mg/kg betamethasone or saline solution either 8 or 15 hours before preterm delivery and postnatal assessment of lung function. RESULTS: After the 15-hour fetal treatment-to-delivery interval, betamethasone-treated lambs had twofold improvement in compliance and lung volumes, a fourfold to fivefold decrease in edema index, and higher blood pressures than saline solution-treated lambs. Postnatal lung function or lung volumes did not improve for the 8-hour treatment-to-delivery interval, although betamethasone decreased the pulmonary edema and increased the postnatal blood pressure. CONCLUSIONS: The minimal interval from fetal exposure to corticosteroids to delivery for improved postnatal lung function was between 8 and 15 hours. Corticosteroid effects on pulmonary edema and blood pressure occurred within 8 hours.     

Blood flow in pulmonary and bronchial arteries in acute experimental pneumonia and pulmonary embolism

Acute lobar pneumonia and pulmonary embolism were induced in rabbits and the blood flow in the pulmonary artery and bronchial arteries was determined using isotopic microspheres. In acute pneumonia the pulmonary artery flow to the involved lung was reduced 8.5 times and the bronchial artery flow was reduced 5.0 times compared to flow in the normal lung. In acute pulmonary embolism, both the pulmonary artery flow (2.3 times) and the bronchial artery flow (2.5 times) were also reduced. For all animals, the reduction in pulmonary artery flow paralleled the reduction in bronchial artery flow (r=0.65).     

Ventilation above closing volume reduces pulmonary vascular resistance hysteresis

The aim of this study was to determine the relationship of pulmonary vascular resistance (PVR) hysteresis and lung volume, with special attention to the effects of ventilation around closing volume (CV). Isolated, blood-perfused canine left lower lung lobes (LLL) were incrementally inflated and deflated. Airway and pulmonary artery pressures (PAP) were recorded after each stepwise volume change. Constant blood flow was provided (600 ml/min) and the pulmonary vein pressure (PVP) was held constant at 5 cm H2O. PAP changes, therefore, were a direct index of PVR changes. Group 1 lobes underwent a full inflation from complete collapse to total lobe capacity (TLC) followed by a full deflation. Group 2 lobes underwent two deflation/inflation cycles, after an initial full inflation. These cycles, both beginning at TLC, had deflation end above and below CV, respectively. Significant PVR hysteresis was noted when the first inflation and deflation were compared. The maximum difference in PAP on deflation was 3.3 cm H2O or 11%. The mean decrease was 2.7 cm H2O for 18 lobes (p < 0.0001). The PAPs on all subsequent inflations or deflations that began above CV remained 9% lower than the initial inflation (n = 9, p < 0.0001), but were not different from each other. However, the final inflation which began from below CV resulted in a 30% return of PVR hysteresis (mean increase in PAP of 0.8 cm H2O, n = 7, p < 0.004). We conclude that there is hysteresis in the PVR response during ventilation, with decreased PVR during deflation relative to the initial inflation, that this hysteresis is absent when lung volume is maintained greater than CV, and that hysteresis returns when inflation occurs after deflation below CV.     

Complete dorsal dislocation of the metacarpophalangeal joint of the thumb

Recent studies using animal models of congenital diaphragmatic hernia (CDH) have reported a reduction in both surfactant (SF) phospholipids and proteins in CDH lungs compared to controls, resulting in biophysical and physiologic impairment of SF function in the hypoplastic CDH lung. Furthermore, SF replacement has been shown to improve physiological function in CDH lungs. Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide whose overproduction has been implicated in the pathogenesis of a number of pathological conditions, such as neonatal and adult respiratory distress syndrome. TNF-alpha has been shown to selectively inhibit the de-novo synthesis of SF phospholipid components in type II pneumocytes. It has been demonstrated that TNF-alpha is synthesized locally in lung and functions in an autocrine/paracrine mode. The aim of this study was to investigate TNF-alpha messenger RNA (mRNA) expression in hypoplastic CDH lung using in-situ hybridization histochemistry, to determine the molecular basis of the SF deficiency in the hypoplastic CDH lung. Lung-tissue samples were obtained at autopsy from 7 full-term newborns (age range: 1-21 days) with CDH and 4 stillborns with CDH. Normal lung tissue from eight infants with sudden infant death syndrome (age range: 5-30 days) acted as controls. In-situ hybridization was performed using TNF-alpha specific and digoxigenin-labeled oligonucleotide probe and visualized by nitroblue tetrazolium staining. In control lung tissue, mRNA expression of TNF-alpha was absent or weak in type II pneumocytes and alveolar macrophages. In contrast, mRNA expression of TNF-alpha was markedly increased in both type II pneumocytes and alveolar macrophages in hypoplastic CDH lung. Our findings of up-regulated TNF-alpha gene expression in CDH lung suggest that the SF deficiency observed in hypoplastic CDH lung may be the result of increased local production of TNF-alpha.     

Differential role of endothelium-derived nitric oxide in the modulation of the systemic and pulmonary circulation in lambs

We have studied the differential role of endothelium-derived nitric oxide (EDNO) in the regulation of the systemic and pulmonary circulations of the lamb. Hemodynamic effects of NG-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg i.v.), an inhibitor of NO synthesis, were determined in juvenile (6 +/- 1 weeks old) lambs, under conditions of basal and elevated vasomotor tone. Under basal conditions, L-NAME raised both systemic (SVR) and pulmonary vascular resistances (PVR) by 20-30% (increasing SVR from 0.318 +/- 0.013 to 0.385 +/- 0.015 mm Hg.min.ml-1.kg and PVR from 0.050 +/- 0.003 to 0.067 +/- 0.010 mm Hg.min.ml-1.kg). When tone was elevated in the pulmonary circulation with hypoxia (PVR was elevated by 60%, from 0.059 +/- 0.010 to 0.094 +/- 0.019 mm Hg.min.ml-1.kg), L-NAME treatment resulted in an augmented increase in PVR (PVR increased by greater than 50% to 0.140 +/- 0.024 mm Hg.min.ml-1.kg). However, when tone was elevated to a comparable degree in the systemic circulation with angiotensin infusion (SVR was elevated by 60%, from 0.432 +/- 0.065 to 0.065 to 0.634 +/- 0.113 mm Hg.min.ml-1.kg), the response to L-NAME was not augmented. Our data suggest that the role of EDNO in the modulation of the pulmonary circulation is dependent on the level of vasomotor tone, whereas its role in the systemic circulation is small and is independent of the level of vasomotor tone.     

Production of pulmonary vasodilation by tolazoline, independent of nitric oxide production in neonatal lambs

OBJECTIVE: To determine whether tolazoline reduces pulmonary vascular resistance (PVR) by means of endogenous nitric oxide production. DESIGN: Thirty newborn lambs (2 to 7 days of age) were anesthetized with pentobarbital, and their lungs were ventilated through an endotracheal tube. Intravascular catheters were placed in the left ventricle, descending aorta, right atrium, and pulmonary artery for continuous monitoring of intravascular pressures. Cardiac output was measured with radiolabeled microspheres. Arterial carbon dioxide pressure and pH were maintained in a normal range throughout the experiments. Animals were randomly assigned to the following groups: group 1, lungs ventilated with a hypoxic gas mixture and administered tolazoline; group 2, given N omega-nitro-L-arginine (L-NA) (5 mg/min intravenously for 60 minutes) and tolazoline; group 3, given L-NA with hypoxia and tolazoline. Acetylcholine (0.5 microgram/kg) was injected into the right atrium to assess pulmonary nitric oxide synthase activity before and after the L-NA infusion. Data were analyzed by analysis of variance. RESULTS: L-NA inhibited the acetylcholine-induced reduction in mean pulmonary artery pressure (MPAP) by more than 75%. Hypoxia and L-NA increased both MPAP and PVR. Tolazoline produced immediate reductions in both MPAP and PVR in all three groups (group 1, 27% +/- 3% and 50% +/- 5%; group 2, 34% +/- 5% and 50% +/- 6%; and group 3, 31% +/- 4% and 46% +/- 5%, respectively). CONCLUSIONS: These results suggest that tolazoline produces vasodilation independent of nitric oxide production. Understanding the mechanism by which tolazoline produces pulmonary vasodilation may provide insight into the clinical use of this drug and information regarding other potential endogenous mediators of pulmonary vasomotor tone in the neonate.     

Phasic flow events at the aortic isthmus-ductus arteriosus junction and branch pulmonary artery evaluated by multimodal ultrasonography in fetal lambs

OBJECTIVES: We assessed the phasic flow and interaction between the pulmonary trunk and aortic isthmus flow at their junction in the lamb fetus in late gestation and also assessed the interaction of the left pulmonary artery branch. STUDY DESIGN: With echocardiographic and Doppler ultrasonographic and saline-contrast techniques, we studied 7 fetal lambs with arterial and venous catheters in place to assess direction, velocity, and timing of flow at the aortic isthmus, ductus arteriosus, and proximal left pulmonary artery. RESULTS: At the isthmus-ductus junction, ductus systolic flow occurred later (0.048 +/- 0.006 second, mean +/- SD) and accelerated more slowly than isthmus flow but with higher velocities (peak 70.7 +/- 7.1 vs 63.1 +/- 6.3 cm/s, velocity time integral 5.7 +/- 1.2 vs 4.5 +/- 1.3 cm, respectively; P <.001). There was a small degree of late systolic flow reversal and admixture from both sources. Signals from the left pulmonary arterial branch showed a sharp, brief systolic forward flow with a peak velocity of 48.8 +/- 9.1 cm/s, followed by late systolic and diastolic flow reversal with a peak velocity of 23.5 +/- 8.7 cm/s. CONCLUSION: The differences in the flow timing may be the result of different timing of ventricular contraction, resistances in the vascular beds, and ductus constriction, both anatomic and physiologic.     

Milrinone improves pulmonary hemodynamics and right ventricular function in chronic pulmonary hypertension

BACKGROUND: Right ventricular failure after cardiac transplantation is commonly related to preexisting recipient pulmonary hypertension. This study was designed to investigate the effects of intravenous milrinone on pulmonary hemodynamic indices and right ventricular function in a canine model of monocrotaline pyrrole-induced chronic pulmonary hypertension. METHODS: Eight mongrel dogs underwent pulmonary artery catheterization to measure right-sided hemodynamic indices before and 6 weeks after a right atrial injection of monocrotaline pyrrole. Six weeks after injection, all hearts were instrumented with a pulmonary artery flow probe, ultrasonic dimension transducers, and micromanometers. Data were collected at baseline and after milrinone infusion. RESULTS: Six weeks after monocrotaline pyrrole injection, significant increases in the pulmonary artery pressure and pulmonary vascular resistance were observed. Milrinone led to significant increases in right ventricular function as well as significant improvements in pulmonary vascular resistance, pulmonary blood flow, and left ventricular filling. CONCLUSIONS: This investigation demonstrates the well-known hemodynamic and inotropic effects of milrinone which, in the setting of monocrotaline pyrrole-induced pulmonary hypertension, were also associated with significant increases in pulmonary blood flow and left ventricular filling.     

Relative effects of cyclooxygenase and nitric oxide synthase inhibition on vascular resistances in neonatal lamb lungs

Effective attenuation of pulmonary vasoconstriction is essential during early postnatal development when increased pulmonary vascular resistance (PVR) may lead to a resumption of right-to-left shunting across fetal channels. In addition, modulation of venous resistance contributes to normal lung fluid balance. This study was designed to identify the relative modulating effects of endothelium-derived nitric oxide (EDNO) and dilator prostaglandins (PG) on normoxic and hypoxic pulmonary vasomotor tone in young newborns. Total and segmental PVR were measured using inflow-outflow and double occlusion techniques in isolated lungs of 6-h-old lambs studied under control conditions or after blocking PG and/or EDNO synthesis with indomethacin and/or N omega-nitro-L-arginine, respectively. During normoxia, both indomethacin and N omega-nitro-L-arginine were required to increase total PVR, but EDNO appeared to have the greater modulating effect. Indomethacin markedly enhanced hypoxic pulmonary vasoconstriction of large and small arteries and small veins, whereas N omega-nitro-L-arginine caused a lesser, but significant, increase in hypoxic pulmonary vasoconstriction of small arteries and veins, suggesting that dilator PG played the dominant modulating role during hypoxia. In addition, PG synthesis appeared to be enhanced after inhibition of EDNO synthesis. In contrast, indomethacin caused a decrease in venous resistance, suggesting that constrictor prostanoids had a greater effect than dilator PG on this segment. EDNO had a modest modulating effect on venous resistance in these lungs. These data suggest that dilator PG and EDNO exert complementary effects in attenuating total and segmental PVR during normoxia and hypoxia in 6-hold lamb lungs.     

A survey of diagnostic practices and the use of epoprostenol in patients with primary pulmonary hypertension

STUDY OBJECTIVE: To obtain information about the diagnosis and management of primary pulmonary hypertension (PPH), especially about the use of epoprostenol (Glaxo-Wellcome; Research Triangle Park, NC) in this patient population. BACKGROUND: Long-term IV epoprostenol therapy was approved recently for use in patients with PPH who are unresponsive to conventional therapy. Although epoprostenol represents a major advance in the treatment of PPH, there is no published consensus regarding the optimal use of this therapy. METHODS: A five-page survey was mailed to 23 investigators at medical centers treating five or more patients with PPH with long-term epoprostenol therapy. RESULTS: Nineteen of 23 investigators responded to the survey. During the initial hemodynamic evaluation, 11 investigators used changes in pulmonary vascular resistance (PVR), pulmonary artery pressure (PAP), and cardiac output, 5 investigators considered PVR and PAP only, and 2 investigators analyzed PVR alone to define a short-term vasodilator response. During long-term therapy, two thirds of the investigators increased the dose at scheduled intervals, while all investigators increased the dose in response to worsening symptoms. Epoprostenol doses were reported to range from 0.5 to 270 ng/kg/min. Nine investigators routinely repeated right heart catheterization an average of 7.5+/-3.8 months after starting epoprostenol, and the mean decrease in pulmonary artery pressure was between 15 and 25%. CONCLUSION: This survey indicates that there is wide variation in the evaluation of patients with PPH and in the use of epoprostenol therapy. The lack of consensus suggests the need for multicenter collaborative studies in order to optimize the use of epoprostenol therapy for PPH.     

Asymmetric distribution of the pulmonary blood flow between the right and left lungs in d-transposition of the great arteries

Pulmonary angiograms, radionuclide lung images and chest roentgenograms were evaluated regarding the incidence, magnitude and natural evolution of maldistribution of the pulmonary blood flow between the lungs in 63 patients with dextrotransposition of the great arteries. Approximately half of these patients had some degree of greater perfusion of the right relative to the left lung. A significant correlation was demonstrated between the incidence of this maldistribution of blood flow and the angulation between the main and the right pulmonary arteries. For any given angulation between these vessels, additional pulmonary stenosis increased the incidence of disparity in perfusion. Our observations suggest the following developmental mechanisms: The maldistribution in flow results from the abnormal rightward inclination of the main pulmonary artery in the transposition malformation which straightens the flow axis from the main to the right pulmonary artery. Under these circumstances the momentum of the blood in the main pulmonary artery carries the blood preferentially into the right pulmonary artery. This momentum is increased when there is stenosis of the left ventricular outflow tract. Consequent differences in the mechanical properties of the two pulmonary vascular beds can increase this maldistribution. The disparity in perfusion between the lungs is not present in newborns with d-transposition, appears to be progressive in severity and in time may result in almost complete cessation of effective perfusion of the left lung. The effect of the Mustard operation on this abnormality of flow is discussed.     

Reconsideration of criteria for the Fontan operation. Influence of pulmonary artery size on postoperative hemodynamics of the Fontan operation

BACKGROUND: The outcome of the Fontan operation largely depends on the selection of patients because this procedure is a physiological correction. Among the several selection criteria for the Fontan operation, the importance of adequate size of the pulmonary artery remains controversial. In this series, in order to clarify whether the pulmonary artery size is indispensable or not as one of the selection criteria for the Fontan operation, we considered the physiological meaning of pulmonary artery size and investigated how it influenced postoperative hemodynamics of the Fontan operation. METHODS AND RESULTS: In congenital heart disease of decreasing pulmonary blood flow, 40 patients were examined for this analysis. Pulmonary artery indexes (cross-sectional area of the right and left pulmonary arteries divided by body surface area) were measured as the expression of pulmonary artery size, and the relations of pulmonary artery index (PAI) to pulmonary vascular resistance (Rp) and compliance (Cp) were studied. There was no significant correlation between PAI and Rp, whereas a significant correlation was found between PAI and Cp (r = .71, P = .001). Furthermore, Cp influenced postoperative hemodynamics of the Fontan operation by affecting the peak central venous pressure (pCVP) and total impedance, which was the afterload to the ventricle. Impedance increased abruptly when PAI was < approximately 100 mm2/m2. CONCLUSIONS: The smaller pulmonary artery size causes more disadvantageous hemodynamics after the Fontan operation, with resultant effects of the rise in pCVP and the increase in afterload to the single ventricle.     

Partitioning of pulmonary vascular resistance in primary pulmonary hypertension

OBJECTIVES: This study sought to determine the site of increased pulmonary vascular resistance (PVR) in primary pulmonary hypertension by standard bedside hemodynamic evaluation. BACKGROUND: The measurement of pulmonary vascular pressures at several levels of flow (Q) allows the discrimination between active and passive, flow-dependent changes in mean pulmonary artery pressure (Ppa), and may detect the presence of an increased pulmonary vascular closing pressure. The determination of a capillary pressure (Pc') from the analysis of a Ppa decay curve after balloon occlusion allows the partitioning of PVR in an arterial and a (capillary + venous) segment. These approaches have not been reported in primary pulmonary hypertension. METHODS: Ppa and Pc' were measured at baseline and after an increase in Q induced either by exercise or by an infusion of dobutamine, at a dosage up to 8 microg/kg body weight per min, in 11 patients with primary pulmonary hypertension. Reversibility of pulmonary hypertension was assessed by the inhalation of 20 ppm nitric oxide (NO), and, in 6 patients, by an infusion of prostacyclin. RESULTS: At baseline, Ppa was 52+/-3 mm Hg (mean value+/-SE), Q 2.2+/-0.2 liters/min per m2, and Pc' 29+/-3 mm Hg. Dobutamine did not affect Pc' and allowed the calculation of an averaged extrapolated pressure intercept of Ppa/Q plots of 34 mm Hg. Inhaled NO had no effect. Prostacyclin decreased Pc' and PVR. Exercise increased Pc' to 40+/-3 mm Hg but did not affect PVR. CONCLUSIONS:ns. These findings are compatible with a major increase of resistance and reactivity at the periphery of the pulmonary arterial tree.     

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.