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Journal of Applied Physiology
Vol. 83, No. 1, pp. 213-218, July 1997
PULMONARY CIRCULATION AND LUNG FLUID BALANCE

Postnatal lung function and protein permeability after fetal or maternal corticosteroids in preterm lambs

Celso M. Rebello, Machiko Ikegami, M. Gore Ervin, Daniel H. Polk, and Alan H. Jobe

Perinatal Research Laboratories, Harbor-UCLA Medical Center, University of California, Los Angeles, School of Medicine, Torrance, California 90502

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Rebello, Celso M., Machiko Ikegami, M. Gore Ervin, Daniel H. Polk, and Alan H. Jobe. Postnatal lung function and protein permeability after fetal or maternal corticosteroids in preterm lambs. J. Appl. Physiol. 83(1): 213-218, 1997.---We evaluated postnatal lung function and intravascular albumin loss to tissues of 123-days-gestation preterm surfactant-treated and ventilated lambs 15 h after direct fetal (n = 8) or maternal (n = 9) betamethasone treatment or saline placebo (n = 9). The betamethasone-treated groups had similar increases in dynamic compliances, ventilatory efficiency indexes, and lung volumes relative to controls (P < 0.05). The losses of 125I-labeled albumin from blood, a marker of intravascular integrity, and the recoveries of 125I-albumin in muscle and brain were similar for control and betamethasone-exposed lambs. Betamethasone-treated lambs had lower recoveries of 125I-albumin in lung tissues and in alveolar washes than did controls (P < 0.01). Although blood pressures were higher for the treated groups (P < 0.05), all groups had similar blood volumes, cardiac outputs, and organ blood flows. Maternal or fetal treatment with betamethasone 15 h before preterm delivery equivalently improved postnatal lung function, reduced albumin recoveries in lungs, and increased blood pressures. However, prenatal betamethasone had no effects on the systemic intravascular losses of albumin or did not change blood volumes.

respiratory distress syndrome; edema; fetal therapy; lung maturation

INTRODUCTION

PRENATAL GLUCOCORTICOID TREATMENTS decrease the incidence and severity of respiratory distress syndrome in clinical trials if the treatment-to-delivery interval exceeds 24 h (19). Epidemiological observations indicate treatment intervals <24 h may also decrease other complications of prematurity such as intraventricular hemorrhage and death (4). We have investigated treatment-to-delivery interval effects after maternal or direct fetal betamethasone treatments in preterm lambs (8, 9, 22). A 15-h direct fetal treatment with betamethasone resulted in postnatal improvements in gas exchange, compliance, and lung volume equivalent to longer treatment-to-delivery intervals (8). In contrast, 8 h of fetal exposure had no effect on postnatal lung function. However the 8-h treatment-to-delivery interval was sufficient to increase postnatal blood pressure and to decrease the vascular-to-alveolar leak of radiolabeled albumin (8). Because fetal treatment with betamethasone results in more rapid and higher elevations of betamethasone in fetal plasma than does maternal treatment (2), we hypothesized that a direct fetal betamethasone treatment-to-delivery interval of 15 h would have an enhanced effect on postnatal lung function relative to maternal treatment. In addition, prenatal corticosteroid exposure increases systemic blood pressure in preterm infants and changes the regulation of vasomotor tone of both systemic and pulmonary vessels in preterm lambs (5, 15, 26). Another consistent effect of prenatal betamethasone is to decrease the loss of intravascular proteins into the lung interstitium and alveoli (8). Therefore, we hypothesized that prenatal betamethasone treatment would decrease the intravascular-to-interstitial movement of albumin in the systemic vasculature as a result of a systemic improvement in vascular integrity.

METHODS

Study groups. Date-mated ewes with singleton fetuses at 122 days gestation (estimated fetal weight of 2.2 kg) were randomized to three study groups. Betamethasone (0.5 mg/kg; Celestone Soluspan, Schering Pharmaceutical) was given to eight fetuses by ultrasound-guided intramuscular injection (8), and the ewes received a saline injection. A second group (n = 9) received maternal betamethasone (0.5 mg/kg maternal weight) and a fetal saline injection (22). A control group of nine ewes received both fetal and maternal injections with saline.

Delivery of preterm lambs and postnatal evaluations. Personnel responsible for management of the animals were unaware of the randomization. Preterm lambs were delivered by cesarean section at 123 days gestation 15 h after treatment. Each ewe was sedated with ketamine (20 mg/kg im), and after spinal-epidural anesthesia (10 ml of 2% lidocaine-0.5% marcaine solution, 1:1 vol/vol) the fetal head was exteriorized through abdominal and uterine incisions (22). The fetus received sedation with ketamine (10 mg/kg im) and acepromazine (0.1 mg/kg im). After local anesthesia with 2% lidocaine, the trachea was exposed and a 4.5-mm-internal diameter tracheal tube was tied into the trachea. Tracheal fluid was aspirated with gentle negative pressure by syringe, and the endotracheal tube was clamped. After delivery, the lamb was weighed and treated with 100 mg/kg of Survanta (Ross Products, Abbott Laboratories, Chicago, IL). Surfactant was given while the animal was rotated through four positions (3). Animals were ventilated for 4 h by using time-cycled pressure-limited neonatal ventilators (Sechrist Industries, Anaheim, CA) with initial settings of 100% inspired O2 fraction, 40 breaths/min respiratory rate, 10 l/min flow, 0.7-s inspiratory time, 0.8-s expiratory time, 35 cmH2O peak inspiratory pressure, and 3 cmH2O positive end-expiratory pressure. Blood gases were measured every 30 min, and peak inspiratory pressures were adjusted to maintain a target PCO2 of ~50 Torr. No other ventilator changes were made. Inspiratory pressures higher than 35 cmH2O were not used to avoid pneumothorax. Tidal volumes were measured with a neonatal pulmonary monitor (model CP-100, Bicore, Irvine, CA), and dynamic compliance was calculated as tidal volume normalized to the body weight divided by the ventilatory pressure, defined as the difference between inspiratory and positive end-expiratory pressures (9). The ventilatory efficiency index (VEI) was used as an integrated measurement of the efficiency of ventilation in the absence of spontaneous breathing (20). VEI was calculated by using the formula VEI = 3,800/(Delta P × PaCO2 × RR), where 3,800 is a CO2 production constant, Delta P is the ventilatory pressure, PaCO2 is the arterial PCO2 in Torr, and RR is the ventilator rate. Supplemental intramuscular ketamine (10 mg/kg im) and acepromazine (0.1 mg/kg im) were given for sedation and analgesia. Body temperature was maintained between 38 and 39°C with radiant heat and a heating pad.

After initiation of ventilation, a 5.0-Fr catheter was placed into the aorta via an umbilical artery and 10 ml/kg of filtered cord blood were given. The catheter was used for blood drawing, arterial pressure recording, and administration of 5% dextrose at 100 ml · kg-1 · day-1. A second 5.0-Fr catheter was placed into the left ventricle through the right carotid artery for administration of radiolabeled microspheres. To measure cardiac output, a known amount of 15-µm-diameter microspheres labeled with 85Sr (Du Pont-New England Nuclear, Boston, MA) was injected into the left ventricle at 2.5 h, and a reference sample was withdrawn from the aortic catheter (21). The relative blood flow, defined as the percentage of the total cardiac output to brain and muscle, was calculated.

After 4 h of ventilation, the animals were deeply anesthetized with pentobarbital sodium (25 mg/kg iv) and the tracheal tube was clamped to allow lung collapse by O2 absorption. A body weight was measured and used for all calculations. The animals were killed by exsanguination by cutting the abdominal aorta. The thorax was opened, the lungs were inflated with air to 35 cmH2O pressure for 1 min, and the volume was recorded. The deflation limb of the pressure-volume curve was measured as the volume of air retained in the lungs at pressures of 20, 15, 10, 5, and 0 cmH2O, after 30 s at each pressure (8). The lungs were removed from the thorax, and alveolar washes with cold saline were repeated five times and pooled (9). Aliquots were taken for saturated phosphatidylcholine (Sat-PC), radiolabeled albumin, and total protein measurements.

Measurements with 125I-labeled albumin. Radiolabeled albumin was prepared by labeling monomer standard bovine serum albumin (Miles Laboratory, Elkhart, IN) with 125I by using chloramine-T (13). Free iodine was removed by dialysis, and incorporation was verified by trichloroacetic acid precipitation. To evaluate loss of radiolabeled albumin from the vascular space and recovery of that albumin in tissues, 10 µCi 125I-albumin were given 3 h after birth via an arterial catheter. Blood samples were taken 45 s and 5, 10, 20, 30, and 60 min after injection for determination of blood volume and the clearance of radiolabeled albumin from blood (7). Aliquots of alveolar washes and tissue from both upper lobes of the lung, the total brain, and the quadriceps muscle were collected after 4 h of ventilation and were analyzed for 125I-albumin recovery. After homogenization in saline, aliquots from tissues were used for measurement of hemoglobin content. On the basis of the amount of 125I-albumin in blood and the amount of blood present in tissues, the amount of 125I-albumin contributed by blood in each tissue was estimated and subtracted (13).

Analytic methods and data analysis. Total protein in alveolar washes was measured by the Lowry assay (17). Sat-PC in alveolar washes and lung tissues was determined for chloroform-methanol (2:1 vol/vol) extracts after treatment with osmium tetroxide and isolation of Sat-PC by column chromatography using alumina (18). Quantification of Sat-PC was by phosphorus assay (1). Plasma cortisol was measured by radioimmunoassay standardized for fetal sheep plasma (10).

All values are given as means ± SE. Between-group comparisons were by analysis of variance, with significance accepted at P < 0.05. The Student-Newman-Keuls multiple-comparison procedure was used as the discriminating test. Two-way analysis of variance with repeated measures was used to evaluate differences in ventilatory pressures, dynamic compliances, and VEIs among the groups with time, and Dunnett's method was used as the post hoc test.

RESULTS

Description of preterm lambs and postnatal lung function. The delivery weights were similar and comparable to the estimated fetal weight of 2.2 kg (Table 1). Therefore, the fetal dose of betamethasone was close to the target dose of 0.5 mg/kg. The lambs had normal pH values in cord blood and after 4 h of ventilation. Blood gas values at 1 and 4 h of ventilation were similar for the two betamethasone-treated groups and the control lambs, demonstrating the ability to achieve similar gas exchange with the ventilation technique used. However, the lambs exposed to fetal or maternal betamethasone required lower ventilatory pressures than did the control lambs (Fig. 1). Relative to control lambs, the betamethasone-exposed lambs also demonstrated higher dynamic compliance values and improved VEI. The improvements in postnatal lung function were equivalent for fetal and maternal betamethasone. Maximal lung volumes averaged 20% higher for the betamethasone-exposed lambs, and lung volumes were higher for each pressure along the deflation limbs of the pressure-volume curves than for the control lambs (Fig. 2). No effect of route of treatment on lung volumes was noted. The amounts of Sat-PC recovered in alveolar washes and lung tissue were similar among groups, with mean values of 15 ± 1 and 54 ± 3 µmol/kg, respectively.

Table  1.   Description of preterm lambs and blood-gas and pH values
Treatment Groups n Gender (M/F) Body Wt, kg pH
PCO2, Torr
PO2, Torr
Cord 1 h 4 h 1 h 4 h 1 h 4 h
Fetal betamethasone 8 5/3 2.1 ± 0.1  7.34 ± 0.01  7.29 ± 0.01  7.30 ± 0.02  50 ± 2  53 ± 2  305 ± 43  324 ± 60 
Maternal betamethasone 9 7/2 2.3 ± 0.1  7.34 ± 0.01  7.30 ± 0.02  7.30 ± 0.01  49 ± 2  51 ± 2  241 ± 30  240 ± 40 
Control 9 2/7 2.4 ± 0.1  7.34 ± 0.01  7.29 ± 0.01  7.27 ± 0.02  54 ± 2  51 ± 2  299 ± 41  187 ± 63
Values are means ± SE; n, no. of lambs. M, male; F, female.

Fig. 1. Ventilatory pressure (A), dynamic compliance (B), and ventilatory efficiency index (C) for preterm lambs. open circle , Control; square , fetal betamethasone; black-triangle, maternal betamethasone. Animals treated with maternal and fetal betamethasone required lower ventilatory pressures to achieve PCO2 of ~50 Torr and had increased dynamic compliances and improved ventilatory efficiency indexes than did control animals (* P < 0.05 vs. control).
[View Larger Version of this Image (24K GIF file)]

Fig. 2. Deflation pressure-volume curves for preterm lamb lungs. open circle , Control; square , fetal betamethasone; black-triangle, maternal betamethasone. Betamethasone treatment by fetal or maternal injection increased lung volumes relative to control animals (* P < 0.05 vs. control).
[View Larger Version of this Image (13K GIF file)]

Intravascular 125I-albumin. The initial half-life of labeled albumin in the intravascular compartment was ~20 min, and the curves over the 60-min study period were not different for the two glucocorticoid-treated groups or the control group (Fig. 3). Extrapolation of the intravascular clearance curves for labeled albumin yielded mean blood volumes of ~90 ml/kg for the three groups. Control lambs had lower blood pressures than did betamethasone-exposed lambs (Table 2). There were no differences in the cardiac outputs among the study groups.
Fig. 3. 125I-labeled albumin in intravascular space. open circle , Control; square , fetal betamethasone; black-triangle, maternal betamethasone. All groups had similar curves for loss of radiolabeled albumin from blood.
[View Larger Version of this Image (16K GIF file)]

Table  2.   Blood volumes and hemodynamic values
Treatment Groups Blood Volume, ml/kg Cardiac Output, ml · kg-1 · min-1 Relative Blood Flow, %cardiac output
Blood Pressure, mmHg
Brain Muscle 30 min 4 h
Fetal betamethasone 92 ± 6  186 ± 11  3.2 ± 0.5  3.1 ± 1.6  57 ± 3  48 ± 1*
Maternal betamethasone 94 ± 5  247 ± 51  3.2 ± 0.5  4.1 ± 0.2  65 ± 3* 49 ± 4 
Control 88 ± 6  168 ± 15  3.6 ± 0.4  1.6 ± 0.6  52 ± 2  42 ± 2
Values are means ± SE. Relative blood flow values are per 100 g of tissue. * P < 0.05 vs. control group.

Recovery of 125I-albumin in tissues. There were no differences in the accumulation of 125I-albumin in muscle or brain between the glucocorticoid-exposed and control lambs (Fig. 4). The relative blood flows to brain and muscle were similar between the study groups (Table 2). Fetal or maternal betamethasone exposure decreased the recovery of 125I-albumin in total lungs, defined as lung tissue plus alveolar wash, from 3.3 to ~2%. The recovery of 125I-albumin in lung was further divided into the tissue and alveolar components (Fig. 5). Maternal or fetal treatment with betamethasone decreased the 125I-albumin recovery in lung tissue and alveolar wash to the same degree. Total protein recovery in the alveolar washes was 76 ± 16 mg/kg for control lambs, 51 ± 8 mg/kg for the fetal betamethasone treatment group, and 56 ± 11 mg/kg for the maternal treatment group, values that were not different.
Fig. 4. Recovery of 125I-albumin in total lung, muscle, and brain tissue. Solid bars, control; open bars, fetal betamethasone; hatched bars, maternal betamethasone. Betamethasone-treated animals had lower recovery of 125I-albumin in total lung compared with control animals (* P < 0.05 vs. control). There were no differences in recovery of 125I-albumin in muscle or brain.
[View Larger Version of this Image (17K GIF file)]

Fig. 5. Recovery of 125I-albumin in lung tissue (hatched bars) and alveolar wash (solid bars). Betamethasone-treated animals had lower recoveries of radiolabeled albumin in lung tissue and alveolar washes compared with control animals (* P < 0.01 vs. control).
[View Larger Version of this Image (30K GIF file)]

Plasma cortisol levels. The control lambs had higher plasma cortisol levels than did animals from both betamethasone-treated groups in cord blood and at 30 and 240 min. Plasma cortisol levels also increased after birth in the control lambs but did not change in the betamethasone-exposed lambs (Fig. 6).
Fig. 6. Plasma cortisol levels for preterm lambs. open circle , Control; square , fetal betamethasone; black-triangle, maternal betamethasone. Both betamethasone-treated groups had lower cortisol levels than did saline-treated animals (* P < 0.01 vs. control). Cortisol increased from cord blood values at 30 and 240 min in control lambs but not in betamethasone-treated lambs (dagger  P < 0.01).
[View Larger Version of this Image (11K GIF file)]

DISCUSSION

This experiment was designed to test two hypotheses: a 15-h fetal betamethasone treatment-to-delivery interval would augment preterm postnatal lung function more than would maternal treatment, and fetal betamethasone exposure would decrease the loss of albumin from the systemic vasculature. We previously found that a single fetal dose of 0.5 mg/kg betamethasone resulted in similar improvements in postnatal lung function (increased compliance, VEIs, and lung volume) for treatment-to-delivery intervals ranging from 15 h to 7 days for lambs delivered at 128 days gestation (8, 9). This dose of betamethasone also improved postnatal lung function within 24 h for lambs delivered more prematurely, at 121 days gestation (3). An 8-h treatment-to-delivery interval did not augment postnatal lung function, but intravascular albumin loss to the lungs decreased and blood pressure increased (8). These results indicate that blood pressure and vascular-to-interstitial albumin loss are early indicators of a fetal response to betamethasone exposure. We recently reported that 0.5 mg/kg betamethasone given to either the ewe or the fetus resulted in an equivalent augmentation of postnatal lung function for a 24-h treatmentto-delivery interval (22). Peak fetal plasma betamethasone levels 3 h after maternal dosing with betamethasone were ~30% of the peak fetal plasma levels achieved 1 h after fetal treatment (2). Clinical data suggest little effect of maternal corticosteroid treatment on the incidence of respiratory distress syndrome for delivery intervals <24 h, although the data for these analyses are confounded by combining all treatment-to-delivery intervals <24 h (4). In the present study, all the physiological variables used to evaluate postnatal lung function improved similarly after fetal or maternal betamethasone treatment despite different peak and time to peak fetal plasma betamethasone levels (2). A likely explanation for the equivalence of response despite the treatment route-dependent differences in time courses of exposure of the fetus to betamethasone is the observation in both sheep and rabbits that lung maturational effects of glucocorticoids seem to either be lacking or complete over a narrow glucocorticoid dose range (14, 24). The different treatment routes also equivalently suppressed cord and postdelivery cortisol levels, responses consistent with comparable fetal effects. Fetal glucocorticoid treatments might enhance postnatal lung function earlier in the interval between 8 and 15 h than do maternal betamethasone treatments. However, we could demonstrate no advantage for fetal betamethasone treatments at the early gestational age of 123 days over maternal treatments for the short treatment-to-delivery interval of 15 h.

Perhaps the most consistent response of the fetal lung to prenatal betamethasone treatment is a decrease in the accumulation of plasma proteins in the interstitium and alveoli (3, 8, 22). Jackson et al. (11) demonstrated the association of proteinaceous alveolar edema with lung immaturity, respiratory distress syndrome, and gas-volume loss. The ventilated preterm lung has increased epithelial and endothelial permeability resulting from the combination of ventilation (volutrama), inflammation, and structural immaturity, depending on the clinical or experimental situation (12, 13). Exposure of the preterm fetal lung to glucocorticoids increased lung gas volume and decreased interstitial and intralobular tissue thickness (16). In the rat, glucocorticoid exposure augmented the transition from double to single capillaries in alveolar walls (25). Maternal betamethasone treatments of rabbits and maternal or fetal treatments of sheep resulted in consistent decreases in the accumulation of intravascular proteins in the lung interstitium and alveoli (6, 22). Although interstitial accumulation of radiolabeled albumin decreased 8 h after treatment in preterm sheep, no effect was noted 4 h after maternal treatment in preterm rabbits (6). The decreased lung endothelial leak of intravascular protein after betamethasone exposure occurred before changes in lung gas volume (8).

It is important to distinguish pulmonary vascular and systemic vascular effects of fetal glucocorticoid exposure. Fetal cortisol infusions result in increased systemic blood pressures but not increased pulmonary arterial pressures after preterm delivery (23). Systemic responses to fetal betamethasone exposure that could affect intravascular protein fluxes are the higher blood pressures (21), increased myocardial contractility, and increased cardiac outputs despite lower plasma catecholamine levels (23). Gao et al. (5) demonstrated changes in the responsiveness of the coronary arteries to nitric oxide after fetal betamethasone exposure. The cardiac effects have been explained in part by enhanced responsiveness of myocardial beta -adrenergic receptors (23). In the present study, the 15-h betamethasone treatment-to-delivery interval had no effect on cardiac outputs or relative blood flows to brain or muscle, although blood pressure was increased. We asked whether the decreased intravascular to lung tissue accumulation of albumin resulting from fetal betamethasone exposure also occurred in the systemic circulation. We found overlapping clearance curves for radiolabeled albumin in blood and equivalent blood volumes at 3 h of age. Recoveries of radiolabeled albumin in two representative tissues, muscle and brain, also were not different. Despite severe immaturity, preterm lambs are not as dependent on intravascular volume infusions for blood pressure regulation as are very preterm infants. Although the intravascular loss of albumin was more rapid in these lambs at 123 days gestation than previously found for 132-days-gestation lambs (7), prenatal betamethasone did not change the net vascular retention of albumin in the systemic circulation of preterm lambs. Effects of prenatal glucocorticoid exposure on systemic vascular integrity have not been evaluated in the preterm infant.

This experiment yielded two new observations about prenatal glucocorticoids. First, single maternal doses of betamethasone 15 h before delivery resulted in improvements in postnatal lung function that were comparable to those achieved with direct fetal treatments of preterm lambs. Second, betamethasone exposure decreased the loss of albumin from the pulmonary vasculature but had no effects on the albumin permeability of the systemic vasculature. These results support the use of maternal corticosteroid treatments for treatment-todelivery intervals of <24 h.

ACKNOWLEDGEMENTS

This work was supported by National Institute of Child Health and Human Development Grants HD-20618 and HD-29713; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil, Scholarship 201607/93-0 (C. M. Rebello); and an Established Investigator Award from the American Heart Association (M. G. Ervin).

FOOTNOTES

Address for reprint requests: M. Ikegami, Children's Hospital Medical Center, Div. of Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039.

Received 10 September 1996; accepted in final form 12 March 1997.

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
R. C. Tan, M. Ikegami, A. H. Jobe, L. Y. Yao, F. Possmayer, and P. L. Ballard
Developmental and glucocorticoid regulation of surfactant protein mRNAs in preterm lambs
Am J Physiol Lung Cell Mol Physiol, December 1, 1999; 277(6): L1142 - L1148.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
D. N. Wells, P. M. Misica, and H. R. Tervit
Production of Cloned Calves Following Nuclear Transfer with Cultured Adult Mural Granulosa Cells
Biol Reprod, April 1, 1999; 60(4): 996 - 1005.
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