Boyd W. Goetzman

Neonatal hypoxia and pulmonary vasospasm: response to tolazoline.

Forty-six neonates with hypoxemia were treated with tolazoline, a pulmonary vasodilator, within the first two days of life. Eight of ten (80%) infants without apparent lung disease responded with a mean increase in PaO2 of 116 torr within one hour of beginning tolazoline infusions. One of the responding infants and two nonresponders died. Thirty-six additional infants with a variety of pulmonary disorders had severe hypoxemia which was refractory to mechanical ventilation. Twenty-one (58%) responded with a mean increase in PaO2 of 130 torr within one hour after beginning tolazoline and 13 (62%) of these survived. Fifteen patients had little or no improvement in PaO2 following tolazoline and only three (20%) of these infants survived. Responders could not be distinguished from nonresponders by clinical or laboratory features prior to therapy with tolazoline. Fourteen infants experienced complications possibly related to tolazoline.

Changes in Endothelial Cell and Smooth Muscle Cell Integrin Expression during Closure of the Ductus Arteriosus: An Immunohistochemical Comparison of the Fetal, Preterm Newborn, and Full-Term Newborn Rhesus Monkey Ductus

Anatomical closure of the ductus arteriosus requires normally quiescent luminal endothelial cells and medial smooth muscle cells to migrate into the subendothelial space forming intimal mounds that eventually coalesce and occlude the vessels lumen. The migration of endothelial cells and smooth muscle cells requires the presence of integrin receptors that interact with the surrounding matrix. We used immunohistochemical staining to examine the repertoires of integrins expressed by endothelial cells and smooth muscle cells during postnatal closure of the ductus arteriosus in full-term and preterm rhesus monkeys. In the fetal ductus, luminal endothelial cells have a limited repertoire of integrins. During postnatal ductus closure, luminal endothelial cells, of both term and preterm monkeys, change their phenotype and express the full repertoire of integrins found on growing capillary endothelial cells (α1β1,α2β1, α3β1,α6β1, αvβ1,α6β4, and αvβ5). Similarly, during ductus closure, smooth muscle cells of both term and preterm monkeys expand their integrin repertoire to include the α5β1 and αvβ3 integrins; these two integrins have been shown to be essential for smooth muscle cell migration in vitro. These changes in integrin profile occur at the same time the endothelial and smooth muscle cells invade their neighboring compartments. In contrast, preterm monkeys with a persistently patent ductus lumen fail to develop these changes in integrin expression and fail to develop neointimal mounds. No evidence of intimal thickening occurs in the absence of changes in integrin expression. Therefore, endothelial cells and smooth muscle cells change phenotypes to produce the intimal thickening required for ductus closure.

Renovascular Hypertension as a Complication of Umbilical Arterial Catheterization

Renovascular hypertension (RVH) in the neonatal period is frequently associated with thromboembolic complications of umbilical artery catheterization. Seven newborn infants with RVH were studied by angiography and/or radionuclide examination. Aortography and, in one case, selective angiography showed variable degrees of renal artery occlusion or attenuation. Thromboembolic defects were frequently present in other vessels. Radionuclide flow studies, renograms, and computer analysis of data (ADAC) demonstrated defects in renal function, indicative of renal ischemia. There was a high degree of correlation between angiographic and radionuclide studies. Successful medical management suggests a more conservative alternative to nephrectomy in the hypertensive newborn.

Percutaneous and Surgical Placement of Fine Silicone Elastomer Central Catheters in High-Risk Newborns

Percutaneous insertion of fine silicone elastomer catheters (0.6 millimeters outside diameter) have been used for central parenteral nutrition of very low birth weight and other high risk infants. Because peripheral venous access can be limited in the newborn, we report the previously undescribed surgical cannulation of the superficial arm veins with this catheter, and compare our experience with this technique and the percutaneous method in neonates. A central catheter position was attained in 88% of surgical (38 of 43) and 74% of percutaneous (17 of 23) cannulations. The two groups did not differ in birth weight or gestational age. The mean duration of catheterization was similar in the two groups (combined means = 21.8 +/- 2.3 days SEM). There was no difference in weight gain (combined means = 16.9 +/- 1.0 grams SEM per day) or head growth (combined means = 1.1 +/- 0.1 millimeters per day) between the groups and these rates approximated known fetal growth rates for our mean gestational age. Disseminated candidiasis, in a 770-gram infant with thymic hypoplasia, caused the only systemic infection and death among our 49 patients. The most commonly encountered problem was catheter occlusion secondary to a blood clot at the tip of these fine catheters (8 of 55). No thromboembolic events were recognized, and minor complications were not different with the two techniques. Surgical cannulation of the superficial arm veins offers a safe alternative to percutaneous central silicone elastomer catheter placement if superficial venous access is not available. Both methods provided early, adequate parenteral nutrition without excessive fluid intake in our high-risk infants, and undoubtedly contributed to a favorable neonatal outcome.

A walking donor program for an intensive care nursery.

Repeated transfusions of small increments of blood are frequently required for the sick newborn infant to correct endogenous hypovolemia and/or to replace blood obtained repeatedly for monitoring purposes. Current practices of blood banks are rarely geared to supply the small amounts of blood used for these individual transfusions. To provide a more efficient system, a walking donor program was established in which an appropriate hospital-based individual is cross matched as a donor for an infant for the duration of the infants hospital stay. The program eliminates wastage of blood and donors and reduces the number of infectious agents to which the infant may be exposed.

DOCUMENTATION OF PRENATAL BRAIN INJURY

The timing of brain injury which leads to neurologic handicap in infants is difficult to establish. However, in infants who die it is possible to estimate the duration of injury by neuropathologic assessment of the state of necrosis, gliosis, alteration of extravascular red cells and calcification.We reviewed the neuropathologic findings, birth history, and clinical course of neonates autopsied at our center during 1982. Five of the 6 term infants and 10 of the 25 premature infants who died at less than 7 days of age were shown to have brain lesions which predated their time of delivery. Two of the 5 term infants and 7 of the 10 preterm infants had Apgar scores of <3 at 1 min and <5 at 5 min of age. Fetal distress was usually unrecognized and only 1 term and 3 preterm infants were delivered by C-section. Clinical characteristics observed did not suggest a recognizable syndrome of prenatal brain injury. However, the gut and lungs had also been affected prenatally in several cases. Respiratory failure was the usual cause of death.We conclude that a number of infants dying at less than one week of age have evidence of prenatal brain injury. Birth asphyxia is frequently associated with this finding and this suggests that such infants do not tolerate labor. The probability of prenatal brain injury in surviving neurologically damaged infants with similar birth histories seems high. The medicolegal implications are important and we recommend careful neuropathological evaluation of all such infants who die.

Hemodynamic responses to angiotensin II in the newborn lamb

Angiotensin II is known to increase both pulmonary and systemic arteriolar tone in adult animals. Its influence on these vascular beds shortly after birth is less well understood. Therefore, we studied the effects of infusions of angiotensin II (0.1 microgram/kg/min) on pulmonary and systemic hemodynamics in 13 anesthesized newborn lambs. Systemic vascular resistance increased significantly from a mean of 0.079 +/- 0.03 to 0.094 +/- 0.04 mm Hg/ml/min during angiotensin II infusion while the mean pulmonary vascular resistance was unchanged at 0.024 +/- 0.01 mm Hg/ml/min. Interestingly, cardiac output increased significantly by 18.9% during angiotensin II infusion. During hypoxemia produced by ventilating with 10-12% oxygen, the responses to angiotensin II infusion were similar to those obtained during normoxia. The absence of an effect on pulmonary vascular resistance and the increase in cardiac output were not predicted based on results reported for older animals. The mechanisms responsible for these age-related differences are unknown. Our findings have implications regarding the potential clinical use of angiotensin II as a modulator of blood pressure in the hypotensive newborn.

1739 THE EFFECT OF PULMONARY HYPERTENSION (PHN) ON LUNG COMPLIANCE (CL) IN NEWBORN LAMBS

Some newborns with PHN appear to have noncompliant lungs until they receive a pulmonary vasodilating drug. We speculate that a stiff, hypertensive pulmonary vasculature may hold the lung in an erect state, thereby decreasing CL. To test this hypothesis, 11 anesthetized and paralyzed newborn (0-3 days) lambs were ventilated at fixed rates and pressures. We instrumented them to measure CL, pulmonary blood flow, and pressures in the pulmonary artery (Ppa), aorta, and left atrium. Pulmonary vascular resistance (PVR) was calculated.In 9 lambs, we induced PHN (10-150% increase in Ppa) with either hypoxia (PaO2 32.5±9.2 torr), infusion of HCl (arterial pH 7.26±0.03), or addition of CO2 to the inspired gas (PaCO2 64.8±14.1 torr, pH 7.21±0.13). Decreases in CL ranged from 7-24%, occured with 47% of the maneuvers, but were unpredictable and correlated poorly with rising Ppa and PVR. However, 2 lambs with unexplained, spontaneous PHN (50-80% increases in Ppa) had 28-36% decreases in CL. Pressure-volume loops from one of these animals are shown at the right.We conclude that PHN may alter CL in newborn lambs, but the mechanism remains unclear. An improved model is needed to elucidate this mechanism.

816 TRACHEAL ASPIRATION AND ITS CLINICAL CORRELATES IN THE EARLY DIAGNOSIS OF CONGENITAL PNEUMONIA

Since the lungs of neonates should be sterile after birth, we investigated the ability of tracheal aspiration to provide early diagnosis of congenital pneumonias. Forty infants presenting with respiratory symptoms and positive chest radiographs by eight hours of age were assigned to control or suspect groups based on the presence of bacteria after sputum analysis. These groups showed no difference in maternal age, parity, duration of membrane rupture or labor, Apgar scores, or birth weight and gestational age. Polymorphonuclear leukocytes (PMNS) were found in 7 of 20 control and 16 of 20 suspect infants. Positive blood cultures were obtained in 1 of 20 control and 14 of 20 infants suspect for pneumonia. Tracheal isolates included Group B streptococci (11), Hemophilus influenzae (2), Escherichia coli (2), Listeria monocytogenes (2), alpha hemolytic streptococci (2), and Staphylococcus aureus (1) in the suspect neonates, and Group B streptococcus from the single control infant. At the time of tracheal aspiration, no statistical differences could be ascertained between the groups regarding pulse, respirations, blood pressure, rectal temperature, pH and base deficit, and corrected absolute numbers of segmented and immature PMNS. The presence of bacteria on histologic analysis of sputum obtained by tracheal aspirate, and the subsequent isolation of a similar bacterium in blood and sputum, provides a valuable tool in the diagnosis of congenital pneumonia when compared to other clinical variables.

DUCTUS ARTERIOSUS ENDOTHELIAL CELLS AND SMOOTH MUSCLE CELLS ALTER THEIR INTEGRIN EXPRESSION TO PRODUCE PERMANENT POSTNATAL CLOSURE. • 1198

Following muscular constriction of the ductus arteriosus in the first hours after delivery, extensive neointimal thickening is required to produce permanent occlusion of the ductus lumen. In premature infants, despite, smooth muscle constriction, neointimal mounds frequently fail to develop, resulting in vessel reopening. Neointimal mounds are formed by luminal endothelial cells(ECs) and medial smooth muscle cells (SMCs) that migrate into the subendothelial space. The migration of ECs and SMCs requires the presence of cell surface receptors (integrins) that interact with the surrounding extracellular matrix (ECM). The ability of the integrin receptors to bind to different ECM molecules is determined by the combination of α and β subunits that make up the integrin receptor. Using immunohistochemical techniques, we examined ductus arteriosus obtained from 4 fetal and 11 four-day-old newborn (3 full-term and 8 preterm [78% gestation]) rhesus monkeys to determine the effects of gestational age on postnatal integrin expression and ductus remodeling. In the fetal ductus, ECs lining the vessels lumen have a limited repertoire of integrins (weak expression ofα1β1 and minimal to negligible expression of otherβ1, β3, β4, β5, andβ6 integrins). In contrast, ECs of capillaries invading the ductus adventitial layer strongly express several integrins(α1β1, α2β1,α3β1, α6β1,αVβ5, α6β4). During postnatal closure, luminal ECs of the full-term ductus change their phenotype and express the identical repertoire of integrins found on migrating capillary endothelial cells. Similarly, after birth, SMCs in the closing ductus change their phenotype and express 2 additional integrins(α5β1 and αVβ3) that we have previously shown to be necessary for SMC migration in vitro. Among the 8 preterm ductus, 3 had lumens that were occluded by neointimal formation; the integrin profiles of the ECs and SMCs of these 3 ductus were identical to those expressed by cells of the full-term postnatal closed ductus. In contrast, 5 preterm newborns with persistently patent ductus lumen failed to develop these postnatal changes in integrin expression and failed to develop neointimal mounds. No evidence of intimal thickening occurred in the absence of changes in integrin expression. These findings show that during ductus closure, ECs and SMCs change their phenotype and express integrins found on migrating cells; this enables them to produce the neointimal mounds necessary for permanent closure.