James J Cummings

Lung fluid balance in lambs before and after premature birth.

The purpose of this study was to see if lung vascular protein permeability is greater in preterm lambs with respiratory distress than it is in lambs without lung disease. We measured pulmonary vascular pressures, lung lymph flow, and concentrations of protein in lymph and plasma of 10 chronically catheterized preterm lambs (gestation 133 +/- 1 d) for 2-4 h before and for 4-8 h after delivery by cesarean section. All lambs were treated with mechanical ventilation after birth and received a constant intravenous infusion of glucose-saline solution at an hourly rate of 10 ml/kg. Respiratory failure developed in six lambs, in which there was a sustained threefold postnatal increase in lung lymph flow and lymph protein flow, with an even greater increase in pleural liquid drainage. Concentrations of protein in lymph and pleural liquid were almost identical, averaging approximately 75% of the plasma protein concentration. In the four preterm lambs without lung disease, lymph flow and lymph protein flow were either near or below fetal values by 6-8 h after birth, and there was little or no pleural liquid drainage. Extravascular lung water averaged 7.3 +/- .8 g/g dry lung in lambs with respiratory failure compared to 4.8 +/- .5 g/g dry lung in lambs without lung disease. Thus, pulmonary edema with abnormal leakage of protein-rich liquid from the lung microcirculation into the interstitium is an important pathological feature of the respiratory disease that often occurs after premature birth.

Intrapulmonary terbutaline and aminophylline decrease lung liquid in fetal lambs.

ABSTRACT: To see if phosphodiesterase inhibition might enhance the effect of β-adrenergic stimulation on fetal lung liquid secretion, we studied the independent and combined effects of intrapulmonary terbutaline and aminophylline on net production of lung luminal liquid over time (Jv) in fetal lambs with chronically placed tracheal loop catheters. We calculated Jv during baseline and experimental periods (90–120 min each) by measuring serial concentrations of 125I-albumin, an impermeant tracer that was well mixed in the luminal liquid. In 21 experiments, tracheal instillation of terbutaline (10-5 M) decreased Jv from 11 ± 1 (mean ± SEM) to −3 ± 2 mL/h. In six other studies, aminophylline (10-3 M) alone had no significant effect on Jv. In 12 experiments, we gave the two drugs sequentially: terbutaline decreased Jv from 11 ± 2 to −3 ± 2 mL/h and aminophylline further decreased Jv to −8 ± 2 mL/h. Amiloride (10-4 M), an inhibitor of epithelial Na+ transport, reversed the combined effect of terbutaline and aminophylline, increasing Jv to 8 ± 1 mL/h. Thus, phospho-diesterase inhibition enhances the β-adrenergic effect of terbutaline on Na+-dependent absorption of liquid from the lung lumen of fetal lambs.

Vasopressin Effects on Lung Liquid Volume in Fetal Sheep

ABSTRACT: The normal switch from placental to pulmonary gas exchange at birth requires rapid removal of liquid from the lungs. Previous reports contend that vasopressin may be important in regulating this process, but this notion derives from studies in which fetal sheep received very large doses of vasopressin that yielded plasma concentrations at least 10 times greater than those that have been measured during normal labor. To study the physiologic effects of vasopressin on lung liquid volume in fetal sheep, we made three sets of experiments. First, we measured plasma vasopressin concentrations [VP] in 15 late-gestation fetal sheep, five of which were at various stages of spontaneous labor. [VP] in these fetuses ranged from < 1 (prelabor) to 31 (during labor) μU/mL; postmortem extravascular lung water (EVLW) ranged from 4.5 to 14.5 g/g dry lung tissue. In a second series of studies, we measured EVLW in five sets of near-term (138 ± 1 d, term = 147 d) twin fetal sheep that received an 8-h i.v. infusion of either isotonic saline (control twin) or AVP (AVP-treated twin) at a rate of (mU/kg)/min. This dose was chosen to mimic [VP] measured in fetuses that had been studied during labor. [VP] did not change in the control twins, whereas [VP] increased from 1.8 ± 1.0 to 27.7 ± 3.5 μU/mL in treated twins. There was a small, statistically significant difference in EVLW between twins that received AVP and untreated twins (11.9 ± 1.8 versus 14.6 ± 2.8 g/g dry lung). In a third series of studies, we measured net production of lung liquid (Jv) by an indicator dilution technique in 16 fetal sheep that received an i.v. infusion of isotonic saline for 2 h followed by AVP for up to 8 h. [VP] averaged 23.4 ± 6.5 μU/mL during AVP infusion. For six fetuses that were studied at < 132 d (128 ± 4 d) gestation, Jv did not change during AVP infusion (11.1 ± 6.7 mL/h versus control, 10.2 ± 4.7 mL/h); for 10 fetuses > 132 d (135 ± 2 d) gestation, Jv decreased from 11.3 ± 4.7 mL/h during the control period to 8.6 ± 5.4 mL/h during AVP infusion. Net secretion of lung liquid did not switch to net absorption in any of the 16 fetuses that received AVP. Thus, i.v. infusion of AVP, at a rate designed to mimic [VP] measured during spontaneous labor, led to modest reductions in Jv and EVLW, but did not cause net absorption of lung liquid in late-gestation fetal sheep.

RANDOMIZED TRIAL OF INHALED (INH) VS INTRA VENOUS (IV) STEROID IN VENTILATOR DEPENDENT PRETERM INFANTS. ▴ 1468

We have previously reported that IV steroid reduces the severity of bronchopulmonary dysplasia in very-low birthweight (VLBW) infants (NEJM 1989; 320:1505). However, adverse effects have been reported. The INH route may maximize pulmonary effects while minimizing systemic effects but there have been no studies comparing INH to IV steroids. We are therefore comparing these two routes in preterm (≤ 30 weeks), VLBW (≤1500 grams) infants who are both ventilator (IMV ≥ 15) and oxygen (FiO2 ≥ 0.3) dependent at 12-21 d of age. From July 10, 1994 to December 1, 1995, 55 infants have been randomized to receive either a 42-day tapering course of IV dexamethasone(n=17), or one of two doses (400 μg daily, n=17; 800 μg daily, n=21) of INH beclomethasone. Baseline FiO2, ventilatory pressure (PIP-PEEP), and mean blood pressure were similar between groups. Baseline mean airway pressure was higher in the IV group, in which two infants required high frequency ventilation. Changes in airway pressures (cm H2O) and blood pressure(mm Hg) are shown below (data from the two INH groups are combined since results were similar): Table

Can Maternal Vitamin E Supplementation Prevent Lung Hypoplasia in the Nitrofen-Induced Rat Model of Congenital Diaphragmatic Hernia?

Recent studies suggest a role for antioxidants in the prevention of pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH). We studied the effects of vitamin E in the nitrofen-rat model of CDH. After an initial fast, timed-pregnant Sprague-Dawley rats were gavage-fed nitrofen at gestational day 11 (term is 22 d). On the same day, one group was given a s.c. injection of vitamin E in alcohol; a second group was given an injection of alcohol alone. A third group received no treatment (control). Fetuses were delivered on day 21, and static pressure-volume curves were measured by immersion. Lungs were analyzed for total DNA and protein content by standard methods. A total of 203 fetuses were studied. Of 151 nitrofen-exposed fetuses, 77% had CDH; 92% of these were right-sided. CDH was present in 82% of vehicle-treated fetuses and 71% of vitamin E–treated fetuses (p = 0.17). Nitrofen-exposed fetuses not only were smaller than control fetuses but also had disproportionately smaller lungs and poorer lung function, even when CDH was absent; however, lung function was worse when CDH was present. Vitamin E treatment did not improve either lung growth or function, although there was a trend toward less CDH. We have shown, for the first time, that the lung hypoplasia seen in nitrofen-exposed rat fetuses is associated with a dramatic reduction in static lung function, even when CDH is not present. Finally, our findings support the notion that lung hypoplasia in the nitrofen-rat model is independent of CDH formation.

Inhaled Nitric Oxide and Methemoglobinemia in Term Infants with Persistent Pulmonary Hypertension of the Newborn

Inhaled Nitric Oxide and Methemoglobinemia in Term Infants with Persistent Pulmonary Hypertension of the Newborn

Prenatal Magnesium Sulfate Exposure and the Incidence of Cerebral Palsy in Very Low Birthweight Infants † 1236

Prenatal Magnesium Sulfate Exposure and the Incidence of Cerebral Palsy in Very Low Birthweight Infants † 1236

Reduction in Lung Liquid Production Caused by Nitric Oxide is Blocked by Methylene Blue. |[dagger]| 1484

We have previously shown that nitric oxide (NO), an important mediator of pulmonary vasodilation at birth, reduces lung liquid production (Pediatr Res 1994; 329A) and that this effect is mimicked by instilling cGMP directly into the fetal lung liquid (Pediatr Res 1997). To further define the role of cGMP in nitric oxide induced reduction in lung liquid, we studied the effects of methylene blue, which inhibits the activation of guanylate cyclase by nitric oxide, on lung liquid production and pulmonary hemodynamics in six chronically instrumented fetal sheep at an average gestational age of 130 ± 4 d. Net lung luminal liquid production (Jv) was measured by plotting the change in lung luminal liquid concentration of radiolabelled albumin, an impermeant tracer that was mixed into the lung liquid at the start of each study. Jv was measured during a 1-2 h baseline, then for 2-3 h following instillation of methylene blue (3 mg), then for 2-3 h following instillation of methylene blue and a 10% saturated nitric oxide solution (5 ml). Results were: (Qp = left pulmonary blood flow; PA=pulmonary artery; CA=carotid artery; LA = left atrium; HR = heart rate):Table Control (saline) instillations (n=8) caused no significant change in any variable. Previous studies using the same dose of nitric oxide resulted in a 75% reduction in Jv. Thus, methylene blue totally blocked the effect of nitric oxide on Jv, supporting the notion that nitric oxide reduces Jv by stimulating guanylate cyclase.

Cyclic Guanosine Monophosphate (cGMP) Reduces Fetal Lung Liquid Production Independent of Changes in Pulmonary Blood Flow. † 1483

Cyclic Guanosine Monophosphate (cGMP) Reduces Fetal Lung Liquid Production Independent of Changes in Pulmonary Blood Flow. † 1483

PULMONARY VASODILATION BY CYCLIC GUANOSINE MONOPHOSPHATE (cGMP) IS NOT ASSOCIATED WITH A REDUCTION IN FETAL LUNG LIQUID PRODUCTION. † 1959

At birth, fetal lung liquid is rapidly removed and pulmonary blood flow dramatically increased. We have previously shown that nitric oxide, an important mediator of pulmonary vasodilation at birth, reduces lung liquid production (Pediatr Res 1994; 329A), but its mechanism of action is unknown. Since nitric oxide causes vasodilation via cGMP, and since other cyclic nucleotides have been shown to decrease lung liquid production (J Appl Physiol 1990; 2054), we studied the effects of cGMP on lung liquid production. Eleven chronically prepared fetal sheep were studied at 129 ± 3 d gestation. Net lung luminal liquid production (Jv) was measured by plotting the change in lung luminal liquid concentration of radiolabelled albumin, an impermeant tracer that was mixed into the lung liquid at the start of each study. Jv was measured during a 1-2 h baseline, then for 2-3 h during an infusion of 8-Br-cGMP (50-200 μg/min), a stable cGMP analog. Infusing 8-Br-cGMP increased left pulmonary artery blood flow from 46 ± 14 ml/min to 84 ± 36 ml/min (P=.001) but had no effect on Jv, which was 19 ± 8 ml/h during the baseline and 20 ± 5 ml/h during the infusion. In our previous studies, a similar increase in pulmonary blood flow induced by nitric oxide was associated with a 75% reduction in Jv. Pulmonary and systemic arterial pressures did not change significantly following the 8-Br-cGMP infusion, although heart rate increased from 159± 11 to 180 ± 22 (P=.007). Control (saline) instillations (n=6) caused no significant change in any variable.