Controversies in management of persistent pulmonary hypertension of the newborn.
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OBJECTIVE: The purpose of the study was to examine the relationship between maternal and fetal acid-base indexes in the baboon. STUDY DESIGN: Eight animals maintained in a tether system were studied during the third trimester. Results were analyzed using analysis of variance. RESULTS: After recovery from surgery, pH in carotid artery blood of the fetus was 7.40 +/- 0.027 (mean +/- SD), PO2, 27.5 +/- 3.45 mm Hg; PCO2, 34.0 +/- 2.37 mm Hg; base deficit, 3.0 +/- 2.15 mEq/L; Hot, 33.4% +/- 2.69% and HbO2, 61.3% +/- 8.65%. The corresponding values in the mother were 7.48 +/- 0.035, 100.7 +/- 9.44 mm Hg, 26.4 +/- 2.95 mm Hg, 3.6 +/- 1.71 mEq/L, 32.6% +/- 4.0% and 97.9% +/- 1.28%, respectively. All indexes remained essentially the same until the onset of active labor, at which time the fetus became slightly acidotic and hypoxemic (pH less than 7.35, HbO2 less than 50%). CONCLUSION: The baboon fetus has slightly higher pH2 and lower PaCO2 than the human fetus and PaO2, base deficit, and maternal-fetal gradients across the placenta in these two primate species are comparable.
Thirty-four infants who had a diagnosis of severe persistent pulmonary hypertension of the newborn at birth (alveolar-arterial oxygen difference greater than 600) were treated without paralysis or hyperventilation to induce alkalosis. All survived. Twenty-seven of these 34 eligible infants (79%) underwent neurologic, intelligence, and audiologic testing between 10 months and 6 years of age. Children who were younger than 1 year of age at the initial hearing test were retested after they reached 2 years of age. The average IQ was within the normal range (mean = 96.23). None had sensorineural hearing loss. Severe neurologic abnormalities were seen in 4 children, 3 of whom had been severely asphyxiated at birth (determined by biochemical criteria). Mild neurologic abnormalities were observed in 5 children. Two infants had bronchopulmonary dysplasia because they required supplemental oxygen for 29 and 66 days, respectively, and had abnormal chest roentgenograms; 1 patient takes intermittent doses of albuterol (Ventolin) and neither currently requires supplemental oxygen. This study of 27 infants with severe persistent pulmonary hypertension of the newborn suggests that conservative management without induced alkalosis or respiratory paralysis is accompanied by no sensorineural hearing loss and a good neurologic outcome.
Experimentally-induced oligohydramnios (oligo) produces lung hypoplasia. To determine if arginine vasopressin (AVP), a hormone known to decrease fetal lung fluid production, contributes to the pathogenesis of oligo-induced lung hypoplasia, the following experiment was performed. Brattleboro rats were mated to produce litters either with AVP [heterozygotes (HZ)] or without AVP [homozygotes (HO)]. On d 15 of gestation, half of each litter underwent amniocentesis to create persistent oligo. Littermates with intact membranes served as controls. Four groups of fetuses, i.e. 10 HO litters divided into control (44 fetuses) and oligo (25 fetuses), and eight HZ litters divided into control (35 fetuses) and oligo (18 fetuses), were killed at term for measurement of organ weights and biochemical determination of lung development. Significant differences between control and oligo groups were observed for body weight (HO, p = 0.008; HZ, p = 0.03), lung weight (less than 0.001 for both crossings), lung/body weight ratio (less than 0.001 for both), DNA per lung (HO, p = 0.02; HZ, p less than 0.001), and lung dry/wet ratio (HO, p less than 0.001; HZ, p = 0.001). Oligo groups with and without AVP were not found to be different for lung weight (p = 0.217), lung/body weight ratio (p = 0.209), and DNA per lung (p = 0.822). An analysis of variance confirmed the lack of any significant difference of the impact of oligo in the presence or absence of AVP. We conclude that AVP plays no role in the development of oligo-induced lung hypoplasia.
A multicenter, prospective randomized controlled trial was performed comparing the efficacy of a single intratracheal dose of modified bovine surfactant extract (Survanta, 100 mg/kg, Abbott Laboratory, North Chicago, IL) with air placebo in preventing respiratory distress syndrome. Infants were enrolled if they were estimated to be between 24 and 30 weeks' gestation, weighed between 750 and 1250 g, and were intubated and stabilized within 15 minutes after birth. A total of 160 infants were treated (79 with surfactant, 81 with air placebo) between 4 and 37 minutes after birth (median time 12 minutes). Of these, 5 infants were excluded from the final analysis. The 72-hour average values for the arterial-alveolar oxygen ratio, fraction of inspired oxygen, and mean airway pressure were calculated from the area under the curve of scheduled values measured throughout 72 hours. Clinical status was classified using five ordered categories (no supplemental oxygen or assisted ventilation, supplemental oxygen only, continuous positive airway pressure or assisted ventilation with intermittent mandatory ventilation less than or equal to 6 breaths/min, assisted ventilation with intermittent mandatory ventilation greater than 6 breaths/min, death). Chest radiographs at 24 hours were graded for severity of respiratory distress syndrome. Infants receiving Survanta had less severe radiographic changes at 24 hours of age and decreased average fraction of inspired oxygen (31% vs 42%, P = .002) compared with control infants. No differences were noted in the average arterial-alveolar oxygen ratio, mean airway pressure, or clinical status on days 7 and 28. A beneficial effect was noted in the incidence of pneumothorax (P = .057) and an increase was noted in the incidence of necrotizing enterocolitis (P = .052). No differences in incidence of patent ductus arteriosus, intraventricular hemorrhage, sepsis, or bronchopulmonary dysplasia were seen. According to results of a secondary analysis, there was improvement in the fraction of inspired oxygen and a greater number of survivors without bronchopulmonary dysplasia in the subgroup of infants weighing less than 1000 g who were treated with surfactant. It was concluded that a single dose of Survanta given shortly after birth resulted in decreased severity of chest radiographic findings 24 hours after treatment and improved oxygenation during 72 hours after treatment, but did not improve other acute measures of disease severity or clinical status later in the neonatal period. The group at highest risk for respiratory distress syndrome (infants with birth weights between 750 and 999 g) may benefit the most from preventive therapy.
The circulating levels of vasopressin, catecholamines and renin activity before, during and following a 10-20% fall in mean arterial blood pressure induced by sodium nitroprusside were measured in six chronically catheterized lambs during the first week of life. No significant changes in pHa, PaO2, PaCO2, Plasma sodium or osmolality were observed during or following the infusion of sodium nitroprusside at an average of 12 g.kg-1.min-1 (table I). However, the fall in blood pressure at the end of 60 minutes infusion, was associated with significant increases in the plasma levels of vasopressin from a control value of 2.4 +/- 0.57 to a maximum of 35.1 +/- 16.3 pg/ml (p = .002), renin activity from 6.7 +/- 1.56 to 27.4 +/- 11.44 ng.ml-1.hr-1 (p = .003), and catecholamines from 189.3 +/- 42.15 to 543.3 +/- 100.52 pg.ml-1 (p = .0001). The increase in vasopressin is lower, while that of PRA was higher and catecholamines similar to those found in the ewe. Plasma renin activity (PRA) and catecholamine levels remained elevated for at least 30 minutes following the end of the infusion while the mean blood pressure rose significantly above control levels and remained elevated for twenty minutes. We speculate that the persistent elevated levels of vasoactive mediators are responsible for the prolonged rebound hypertension following the cessation of the nitroprusside infusion and is the result of an immaturity of either a feedback process or metabolism of the vasoactive mediators or a combination of both mechanisms. This rebound hypertension could have adverse effects particularly in the very immature neonate.
A tether system, conditioning procedures and surgical techniques were designed to maintain chronic catheters and electrodes in the pregnant baboon and her fetus. The tether system was comprised of a lightweight metal backpack containing catheters and electrodes, couplers, pressure transducers and electrical cabling. The backpack was held snugly in place by shoulder and body straps. A flexible metal tether connected the pack to a ball bearing assembly mounted on the top of the animal's home cage. Attached to the assembly were two infusion pumps, fluid reservoir and slip ring electrical connector. The entire system rotated freely with the movements of the animal; thus, the instrumentation and connectors were secure while access was maintained for continuous physiologic recording and intravascular infusion or intermittent blood sampling with minimal physical restraint. Animals were conditioned to accept the system prior to pregnancy and animals who demonstrated tolerance were bred. An initial group of 10 pregnant animals were sham tethered during pregnancy at 102 +/- 7 days with term gestation estimated at 180 days. Surgical procedures were done at 136 +/- 4 days with placement of catheters in the maternal femoral artery and vein, fetal carotid artery jugular vein and trachea, amniotic fluid cavity, and electrodes for fetal electrocardiogram and electroencephalogram. The mean fetal survival time was 9.3 (range 0 to 29) days. The major complications which led to early delivery were placental abruption and rupture of amniotic membranes. With ultrasonic localization of the placenta and determination of fetal position before surgery, these complications may be avoided.(ABSTRACT TRUNCATED AT 250 WORDS)
The release of vasopressin, renin, and catecholamines by the fetus during either maternal or fetal hypotension was examined in chronically catheterized fetal lambs. Nitroprusside was infused intravenously for 1 h into seven pregnant ewes (maternal hypotension) or nine fetal lambs (fetal hypotension); the rates were adjusted to achieve a 15 to 30% decrease in mean blood pressure. During maternal hypotension, mean +/- SE vasopressin in maternal plasma increased from 1.2 +/- 0.2 pg.ml-1 to 208 +/- 153 pg.ml-1 and plasma renin activity increased from 1.5 +/- 0.3 ng.ml-1.h-1 to 6.6 +/- 1.6 ng.ml-1.h-1. Fetal vasopressin and plasma renin activity also increased during the same interval from 1.1 +/- 0.3 to 16.9 +/- 7.5 pg.ml-1 and 3.7 +/- 1.1 to 10.5 +/- 2.85 ng.ml-1.h-1, respectively; but no changes were observed in fetal blood pressure, heart rate, or acid base status. During fetal hypotension, mean vasopressin in fetal plasma increased from 4.3 +/- 3.4 pg.ml-1 to 1054 +/- 772 pg.ml-1, plasma renin activity increased from 5.7 +/- 2.2 ng.ml-1 to 22.2 +/- 7.1 ng.ml-1.h-1, and total catecholamines from 174 +/- 58 pg.ml-1 to 810 +/- 416 pg.ml-1. There was no change in fetal heart rate, acid base status, osmolality, or sodium concentration. The fetus became and remained hypertensive for at least 1 h after the end of infusion. This prolonged hypertension was associated with elevated levels of vasopressin and plasma renin activity. Peak vasopressin levels were proportional to the total nitroprusside dose in both the ewe and fetus (maternal r = 0.796, fetus r = 0.870).(ABSTRACT TRUNCATED AT 250 WORDS)
Fetal tcPo2 levels were measured in 10 patients following maternal administration of 50 mg of meperidine by intravenous route. About 3 minutes following injection of meperidine, tcPo2 values started to decline to reach the lowest value of 37 +/- 25% by 7 mins of injection. tcPo2 values recovered by about 15 mins following injection. These changes in fetal tcPo2 levels preceded transient minimal increase in FHR variability. The increase in FHR variability was followed immediately by a decrease in the indices of the FHR variability. The uterine activity began to decline below the predicted positive slope values shortly following injection of meperidine. This decline was maximum 15 mins post-injection, subsequently establishing a trajectory toward the positive values expected for unmedicated labor. Two patients receiving 25 mg intravenous meperidine demonstrated no decline in tcPo2 levels; however, in the patient receiving 75 mg of intravenous meperidine, the changes noted were similar to those observed following 50 mg of meperidine.
We present an experience with indwelling peripheral arterial catheters in preterm and term neonates. During a 12-month interval, 158 peripheral arterial lines were inserted in 115 infants. Eighty-eight infants required a single line while 27 infants required more than one line. Ninety-one catheters (57.6%) were electively removed, and 67 (42.4%) had to be discontinued prematurely. Vessels used included 110 radial arteries (69.6%), 27 posterior tibial arteries (17.1%), and 21 temporal arteries (13.3%). There were only two major complications (1.27%), both related to infections. The technique is described in detail. In our experience, with appropriate precaution, peripheral arterial cannulation has been a safe and reliable alternative to umbilical arterial catheterization.
Pulmonary function was measured in 18 children aged 6 to 9 years who had been born prematurely (mean birth weight 1760 +/- 555 g) and who had each received greater than 100 hours (mean 177 +/- 74 hours) of mechanical ventilation for respiratory distress syndrome (RDS). We used as controls 26 children aged 6 to 7 years who had been born prematurely (mean birth weight 1636 +/- 554 g) but who had required no treatment for pulmonary disease. Results for total lung capacity, FEV1, ratios of functional residual capacity and residual volume to total lung capacity, specific airway conductance, and alveolar plateau slope did not differ in the RDS and control groups. Eight of the 18 children in the RDS group had had radiologic evidence of bronchopulmonary dysplasia at 30 days and oxygen dependence at 30 days, but did not differ from the control group for any of the indices of pulmonary function. However, FEV1 and specific airway conductance were significantly reduced in the premature control group compared with children born at term. Therefore, factors associated with prematurity rather than combined effects of RDS and its treatment determined pulmonary function at age 6 to 9 years.
We drained the amniotic fluid surrounding guinea pig fetuses between days 45 and 65 of gestation (term is 67 days). The fetuses were delivered by Cesarean section and the impact of prolonged oligohydramnios on lung growth, maturation and postnatal ventilatory pattern was measured. Untouched littermate fetuses served as controls. Neither fetal body, liver nor brain weights were significantly affected by the experimental situation. When expressed in percent of control values, lung weight (63%), lung/body weight ratio (70%), lung volume (67%), total lung DNA content (63%) and lung DNA per gram of fetal weight (71%) were all significantly less following amniotic fluid drainage, confirming the diagnosis of lung hypoplasia. Disaturated phosphatidylcholine content per gram of lung tissue and total lung glycogen content were not affected by the procedure, indicating that the maturity of the hypoplastic lungs was not delayed. When measured 4 to 6 hours after birth, tidal volume was significantly less (62%) and respiratory frequency was significantly more (137%); however, minute ventilation per unit of body weight was not significantly changed. This animal model of sublethal lung hypoplasia could become useful to study the potential for, and the kinetics of, postnatal catch-up lung growth about which little is known.
The structural development of the fetal guinea pig lung is described and quantified morphometrically in this report. At 35 days gestation the lung is in the pseudoglandular phase of growth, by 40 days it is in the canalicular phase, and at 50 days the saccular growth phase has begun. At term (67 days), the fetal guinea pig lung appears mature. From the beginning of the canalicular to the end of the saccular phases, the correlation coefficient between lung volume and gestational age is +.98, between internal surface area and gestational age is +.94 and between total number of saccules and gestational age is +.97. Internal surface area (ISA) correlates closely with lung volume (r = +.99) and the correlation coefficient between total number of saccules and lung volume is +.98. At term, lung volume is 4.22 ml. ISA is 0.5 M2, and total number of saccules is 253 million. Parenchymal growth is achieved by increases in both number and size of airspaces in the canalicular phase, primarily by increases in number during the early saccular phase and largely by increases in airspace size near term. The total length of parenchymal elastic tissue increases from 223 M at 45 days gestation to 5,253 M at term. Elastic tissue fibers first appear in the parenchyma of the fetal guinea pig lung during the canalicular phase, when the rate of saccule formation is high. The quantitative increase in elastic tissue correlates closely with the increase in the total number of saccules from day 45 to day 60 of gestation (r = +.99). The rate of elastic tissue growth increases sharply in the late saccular phase, coinciding with the period of greatest saccular expansion. These data suggest an interdependent relationship between saccular growth, i.e., proliferation and expansion, and the development of lung parenchymal elastic tissue.
The characteristics of a microcomputer-based system for measuring ventilatory parameters in neonates on mechanical ventilatory assistance are described. The tidal flows of the infant are sensed by a pneumotachometer housed in the wall of a constant pressure plethysmograph. The processed signal from the pneumotachometer is fed to a dedicated analog-to-digital converter and 6502 microcomputer, which, in turn, loads a dual ported RAM buffer with smoothed, digitized, tidal flow data. At the end of each minute the Apple 2+ processes the accumulated data and computes tidal volume, respiratory frequency, minute volume and the difference between inspired and expired volume. Numerical outputs for these variables and a histogram, representing the distribution of tidal volumes for the minute, are printed on a dot matrix printer. This inexpensive system is capable of presenting contemporary, summarized, ventilatory data in a form that is potentially very useful for the clinicians who are managing the care of the infant.
We drained amniotic fluid for periods of 5 and 10 days at various times in gestation between days 40 and 55 in the guinea pig (term is 67 days). We analyzed the impact of this procedure on fetal lung growth and used untouched littermate fetuses as controls. During the canalicular stage of lung development, total lung DNA per gram of fetal weight was significantly reduced after only 5 days of oligohydramnios and the percent change did not vary between the two consecutive 5-day periods studied (period A, days 40 to 45, delta of -0.047 mg, p = 0.004; period B, days 45 to 50, delta of -0.042 mg, p = 0.002). The impact of the same duration of oligohydramnios on lung growth later in gestation, during the terminal sac stage of lung development, was less (period C, days 50 to 55, delta of -0.027 mg, p = 0.097). This reduction in effect between period A or B and C was significant at the 0.05 level using a one-way analysis of variance. Two overlapping 10-day periods were also studied. In both experiments, the percent changes in lung DNA per gram of fetal weight between experimental and littermate controls were significant (period D, days 40 to 50, delta of -0.072 mg, p = 0.001; period E, days 45 to 55, delta of -0.047 mg, p = 0.001). The inhibitory effect of oligohydramnios on lung growth was more marked in period D than E (significant at the 0.05 level).(ABSTRACT TRUNCATED AT 250 WORDS)
Deficient quantity of amniotic fluid causes fetal guinea pig lung hypoplasia. Oligohydramnios that lasts only 5 days in early gestation is sufficient to reduce fetal lung growth significantly. We quantitated lung structural alterations at 50 days gestation (term is 67 days) of fetal guinea pigs whose amniotic fluid was drained on day 45 gestation. The study period spans the late canalicular-early saccular phases of guinea pig lung growth. Compared to littermate controls (n = 4), experimental fetuses (n = 5) have reduced lung:body weight ratio (2.81 +/- 0.16 versus 3.21 +/- 0.20 X 10(-2), p less than 0.01), indicating lung hypoplasia. Lung volume is significantly decreased in the experimental fetuses (1.17 +/- 0.15 versus 1.34 +/- 0.07 ml, p less than 0.05). The proportion of lung containing parenchyma (i.e. developing alveoli and alveolar ducts) is reduced following oligohydramnios (0.83 +/- 0.04 versus 0.90 +/- 0.02, p less than 0.025). The hypoplastic lungs contain fewer saccules (fetal "alveoli") (46 +/- 20 versus 69 +/- 23 X 10(6), p less than 0.1) and the surface area that would be available for gas exchange is decreased (698 +/- 234 versus 974 +/- 80 cm2, p less than 0.05). Lung volume and volume proportion of parenchyma are reduced in the experimental lung and therefore diminished parenchymal elastic tissue is anticipated. However, the total length of parenchymal elastic tissue in the experimental lungs is decreased to a surprising degree and is little more than half the length in control lungs (504 +/- 222 versus 974 +/- 70 m, p less than 0.0025). Such marked reduction in total length suggests that factors other than smaller lung size have contributed to the decrease of elastic tissue in the experimental group. In fact, elastic tissue length per unit volume is significantly reduced (509 +/- 189 versus 809 +/- 115 m/cm3, p less than 0.025) indicating an absolute decrease in parenchymal elastic tissue in the hypoplastic lungs.(ABSTRACT TRUNCATED AT 250 WORDS)
Our recently reported animal (rat) model of maternal cigarette smoke exposure during pregnancy is characterized by fetal growth retardation and lung hypoplasia. We have further defined the fetal lungs using quantitative histologic techniques. Compared to controls, lung volume at term is reduced in the experimental animals (0.28 versus 0.33 ml, p less than 0.005). Saccules (fetal "alveoli") are reduced in number (3 X 10(6) versus 5.5 X 10(6), p less than 0.005) and increased in size (average saccular volume: 35 X 10(-9) versus 21 X 10(-9) ml, p less than 0.025). These changes in size and number are consequences of reduced formation of saccule partitions (septal crests) in the experimental lungs (volume density: 0.013 versus 0.018, p less than 0.025). Internal surface area is decreased in the hypoplastic lungs (161 versus 198 cm2, p less than 0.001). The total length of parenchymal elastic tissue is diminished (224 versus 354 M, p less than 0.05). In short the hypoplastic lungs contain fewer, larger saccules and the surface potentially available for gas exchange is reduced. These results show that maternal smoking in rats adversely modifies fetal lung growth. If these observations are applicable to humans, then reduced lung growth in children of smoking mothers may begin antenatally.
The concentrations of vasopressin in the plasma and cerebrospinal fluid (CSF) of the chronically catheterized fetal lamb were measured under basal and hypoxic conditions. Under basal conditions, samples were obtained from 13 fetal lambs of 117-146 days gestation. The mean +/- SEM vasopressin level in CSF was 19.5 +/- 1.5 pg/ml; the mean plasma vasopressin level of 1.9 +/- 0.2 pg/ml was significantly less (P less than 0.001). No consistent change in concentrations of vasopressin in CSF was observed with gestational maturation in 3 animals sampled sequentially or in individual samples obtained over the last 32 days of gestation. The mean vasopressin concentration in the CSF of the pregnant ewe was 5.1 +/- 0.4 pg/ml. The gradients for osmolality, sodium, and potassium between fetal plasma and CSF were: osmolality, 298.4 +/- 1.6 to 304.3 +/- 1.4 mosmol/kg; sodium, 140.9 +/- 0.5-142.5 +/- 0.5 meq/liter; and potassium, 4.3 +/- 0.1 to 3.3 +/- 0.1 meq/liter. Fetal hypoxia was induced by exposure of the ewe to 10% O2 in N2 for 30 min. The concentration of vasopressin increased from 1.7 +/- 0.3 to 277 +/- 144 pg/ml (P less than 0.001) in fetal plasma and from 21.4 +/- 3.8 to 47.1 +/- 9.9 pg/ml (P less than 0.04) in fetal CSF. When the ewe was exposed to room air under comparable experimental conditions, no similar changes in plasma or CSF vasopressin levels were observed in the fetus. Infusion of vasopressin into the fetal jugular vein at 1.0 mU/min for 30 min increased plasma concentrations from 2.3 +/- 0.5 to 83 +/- 17 pg/ml, while the CSF vasopressin values were 31.9 +/- 5.9 (basally) and 30.7 +/- 4.8 pg/ml (after infusion). Mean plasma and CSF osmolality, sodium, and potassium were not changed by any of these experimental interventions. We conclude that 1) under basal conditions, high concentrations of vasopressin are present in the CSF of the fetal lamb, the blood-CSF barrier appears to be impermeable to vasopressin, and concentrations of the hormone in fetal plasma are less than those in CSF; and 2) hypoxia is a potent stimulus of vasopressin release in both fetal plasma and CSF. The route of vasopressin released into the fetal CSF may be distinct from that released into plasma.