Michael A. Heymann

Blood flow measurements with radionuclide-labeled particles.

When appropriately and correctly applied, the microsphere technique is relatively simple and extremely accurate. Distribution patterns, both of total systemic arterial blood flow or venous return as well as within specific organs, can be measured. Several techniques have been applied to quantitate flow using microspheres; the reference sample method is extremely simple and by far the most accurate of all. Collection of venous effluent is perhaps more accurate but requires extensive surgery and is almost certainly the least physiologic. Other methods used for quantitation, such as bolus injections of indocyanine green dye or in fusions of diffusable indicators, are considerably less accurate and therefore significantly reduce the reliability of the microsphere technique. Selection of the appropriate size microspheres allows for definition of arteriovenous anastomoses as well as the measurement of organ blood flows and distribution of blood flow within those organs. In most instances, smaller microspheres (15mu diameter or 8-10mu diameter) have significant advantages over larger ones. They are distributed more like red cells, obstruct less of the vascular bed, are less variable in size, and can be given in significantly greater numbers. This latter point is important, since the statistical criteria need to be satisfied and the use of small spheres allows for the more reliable measurement of blood flow to small organs or to small regions of organs.

The Circulation of the Fetus in Utero Methods For Studying Distribution of Blood Flow, Cardiac Output And Organ Blood Flow

Techniques are described for insertion of vinyl catheters into the umbilical and limb vessels of the fetus of the sheep or the goat through small uterine incisions, with the ewes under spinal analgesia. The catheters are exteriorized and the fetus can be studied in its normal intrauterine environment. During constant infusion of antipyrine into a fetal limb vein, placental arteriovenous difference of antipyrine was measured, and fetal umbilical blood flow was calculated by the Fick method. “Carbonized” microspheres (50-μ diameter) labeled with various nuclides were injected into different venous sites in the fetus. The distribution pattern of the microspheres was used to determine the relative distribution of blood flow. Experimental evidence is provided that (1) there is no significant recirculation of microspheres, (2) the distribution of spheres is proportional to flow, and (3) circulatory physiology is not altered by injection of spheres. Quantitative data on the distribution of umbilical venous and superior and inferior vena caval return were obtained. It was possible to determine the actual blood flow to each of the fetal organs by relating the proportions of nuclide in each organ to that in the placenta. Total cardiac output was then calculable, taking into consideration the hemodynamic arrangement of the fetal circulation.

INHALED NITRIC OXIDE AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Background Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. Methods In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. Results Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. Conclusions Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Cardiovascular responses to hypoxemia and acidemia in fetal lambs

Abstract Circulatory responses to hypoxemia and acidemia were studied in 10 fetal lambs in utero with gestational ages of 122 to 142 days. Vinyl catheters were placed in fetal and maternal vessels, and the fetuses were studied 2 to 5 days postoperatively. Fetal heart rate, arterial pressure,Po 2 ,Pco 2 , and pH were measured during a control period and while the standing ewe breathed 6 per cent oxygen and 3 per cent carbon dioxide through a plastic bag over its head. Fetal cardiac output and distribution and absolute organ blood flows were calculated from injections of 15μ nuclide-labeled microspheres, during the control and hypoxemic states. One group of 5 fetuses only became hypoxemic (meanPo 2 12 and mean pH 7.36), but the other 5 fetuses also developed acidemia (meanPo 2 12 and mean pH 7.28). Fetal arterialPco 2 values were normal throughout. During hypoxemia, fetal arterial pressure increased, and fetal heart rate decreased. Although cardiac output fell in all but one fetus, the decrease was significant only in the acidemic group. Blood flow to the fetal body decreased in all, but the change was significantly greater in the acidemic group. Umbilical blood flow was maintained in all fetuses during hypoxemia. The per cent distribution of cardiac output to the placenta rose from 41 to 48 per cent and from 41 to 57 per cent in the hypoxemic and acidemic groups, respectively. Blood flow to the brain, heart, and adrenals increased two- to three-fold in all fetuses during hypoxemia while pulmonary, renal, splenic, gut, and carcass flows decreased. The changes were of greater magnitude in fetuses with combined hypoxemia and acidemia. These studies quantitate the fetal circulatory changes that occur in unanesthetized fetal lambs in utero during maternal hypoxemia.

Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis.

Inhibition of prostaglandin synthesis constricts the ductus arteriosus in fetal lambs in utero. We administered the inhibitors, aspirin or indomethacin to 18 premature infants with patent ductus arteriosus, and assessed the effects clinically and by echocardiography (left atrial/aortic-root ratio). After aspirin (20 mg per kilogram, every six hours for four doses) the ductus closed permanently in one infant within 24 hours; in another, constriction occurred with clinical improvement, and the third did not respond. In five infants given 0.3 mg per kilogram of indomethacin, complete closure occurred within one day; two of them, who received three doses had an elevated serum creatinine for one week. In one infant the ductus reopened, requiring a second dose of indomethacin 11 days after the first. Ten infants received 0.1 mg per kilogram of indomethacin, and closure occurred within 24 to 30 hours in eight. One had a soft murmur for four days, and one did not respond to two doses of indomethacin. A murmur reappeared after three to seven days in three infants but only one required further treatment. In infants receiving a single dose of 0.3 mg per kilogram, or one or more doses of 0.1 mg per kilogram, renal function was unaltered.

Circulatory Changes during Growth in the Fetal Lamb

The changes in circulation with advancing gestation were investigated in 44 fetal lambs in utero; gestational ages ranged from about 60 days to 150 days. Spinal analgesia was administered to the ewe, polyvinyl catheters were inserted into fetal vessels, and umbilical blood flow was measured by the steady-state diffusion Fick method during antipyrine infusion. Cardiac output, distribution of cardiac output, and actual organ blood flows were calculated from injections of nuclide-labeled microspheres (50μ diam) into a forelimb and into an umbilical or hindlimb vein. Umbilical Po2, Pco2 and pH did not change significantly during gestation. Umbilical blood flow and total cardiac output increased in proportion to fetal weight. The proportion of the combined ventricular output distributed to the placenta decreased from about 50% in the youngest fetuses to about 40% just before term. The proportion of the cardiac output distributed to the lungs, as well as the actual flow in relation to lung weight, increased throughout gestation, with a more rapid rise after about 120 days. There was also a late increase in intestinal flow. Cerebral blood flow increased gradually throughout gestation, both as a proportion of cardiac output and in relation to brain weight. There were no significant changes in percent of cardiac output, or flow related to weight in the kidney, heart, or skin and muscular tissues. The studies suggest that, since lung blood flow is a relatively small proportion of total cardiac output, it is not important in regulating distribution of blood flow, but that the peripheral circulation in skin and muscle, which receives a large percent of fetal cardiac output, is the site where vasomotor responses may effect major redistribution of the fetal circulation.

Hemodynamic considerations in the development of narrowing of the aorta

Abstract In the normal fetus the level of blood flow across the aortic isthmus is lower than after birth. This is reflected by a smaller diameter of the isthmus in relation to the ascending and descending aorta. We postulated the effects of various congenital heart lesions on aortic isthmus development in the fetus on the basis of assumed changes in flow patterns. These alterations have been confirmed by studies of cineangiograms in newborn infants. In congenital heart lesions with reduced pulmonary arterial outflow, the diameter of the aortic isthmus is wider than normal, presumably because it carries a greater than normal flow in the fetus. In lesions interfering with left ventricular outflow the aortic isthmus may be underdeveloped. However, in aortic atresia the isthmus is normally developed since it carries a normal flow but in a retrograde manner. We reviewed the clinical data and angiograms of 41 infants less than 3 months old who had aortic obstruction. They could be divided into 2 distinct groups. Twenty-three with aortic isthmus narrowing or interruption had a large ventricular septal defect and a high incidence of complex anomalies such as double outlet right ventricle. The remaining 18 infants with localized juxtaductal narrowing had a low incidence of associated intracardiac lesions. The appearance of the localized juxtaductal coarctation suggested that aortic obstruction may not be present during fetal life because the widely patent ductus arteriosus obviates aortic obstruction. We postulated that constriction of the ductus arteriosus after birth would produce obstruction. This was confirmed experimentally in fetal lambs with surgically simulated juxtaductal coarctation.

The independent effects of hyperventilation, tolazoline, and dopamine on infants with persistent pulmonary hypertension

We studied the separate and combined effects of hyperventilation and administration of dopamine and tolazoline in five infants with pulmonary hypertension managed with indwelling pulmonary artery catheters. In five infants the right-to-left shunt reversed during ventilator-induced respiratory alkalosis (pH greater than 7.6). Response to drugs was variable and unpredictable. One infant could be oxygenated at normal pH during combined dopamine and tolazoline infusion. Other infants showed no response to drugs, or became worse during infusion. The ratio of pulmonary artery to systemic artery pressure averaged 1.14 with standard therapy, but decreased to 0.98 following respiratory alkalosis alone, to 0.87 following drug infusions, and to 0.70 following the combination of alkalosis and drug infusion. These changes were significant by analysis of variance at P less than 0.02, P less 0.001, and P less than 0.001, respectively. Systemic oxygenation was satisfactory in all cases when the pulmonary to systemic pressure ratio was less than 1.0.

Persistent pulmonary hypertension of the newborn infant

Persistent pulmonary hypertension of the newborn infant can be difficult to distinguish from other cardiopulmonary causes of cyanosis during the newborn period. Infants with PPHN have cyanosis, tachypnea, acidemia, normal pulmonary parenchymal markings on the chest radiography, and anatomically normal hearts. We have identified and treated 11 infants and have noted several signs and symptoms not previously emphasized. These are cineangiocardiographic evidence of atrioventricular valve insufficiency in association with systolic murmurs and slow ventricular emptying, apnea, hypocalcemia, only a small rise in abdominal aortic blood oxygen tension during breathing of 100% oxygen, and no response to continuous positive airway pressure. Right-to-left shunting through the patent ductus arteriosus was documented in nine infants: in all six of those in whom simultaneous temporal and abdominal aortic blood oxygen tension measurements were made; in three by means of cardiac catheterization. Ten infants survived after variable courses and treatments which makes it difficult to ascribe improvement to any one therapy. The distinct increase in blood oxygen tension with tolazoline HCl and curare in some instances is discussed.

Patent ductus arteriosus in premature infants.

Abstract Patent ductus arteriosus (PDA) developed in 17 of 111 premature infants (birth weight 1750 g or less) born during a four-year period (15.3 per cent incidence). During that time we treated 29 such infants, 17 born at our own institution and 12 similar infants transferred from other hospitals. Sixteen of the 29 had cardiac catheterization, 10 had operative closure of the PDA, and 24 survived. When the PDA became evident, 23 infants had no pulmonary disease, were recovering from the idiopathic respiratory-distress syndrome (IRDS) or had chronic lung disease; all survived. In six infants with severe IRDS, onset of PDA was associated with a worsening of the pulmonary status; only one survived. We recommend cardiac catheterization and operative closure of the PDA in neonates when heart failure cannot be controlled medically. The prognosis is good in infants in whom onset of PDA is not associated with progressively worsening IRDS.