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Human
Development,
29 (1992)
283
283-286
Elsevier Scientific Publishers Ireland Ltd. EHD 01289
Prenatal prevention of respiratory distress syndrome: new pharmacologic approaches Ermelando V. Cosmi 2nd Institute
of Obstetrics
and Gynecology,
University
‘La Sapienza’,
Rome
(Italy)
Summary
A deficit of lung surfactant is known to be involved in the pathophysiology of the respiratory distress syndrome of the neonate (RDS), which is still responsible of about one fourth of total neonatal mortality. It has been well documented that maternal administration of corticosteroids enhances fetal lung maturity, promoting synthesis of surfactants and altering also the structure of the lung parenchyma. Although the beneficial effects of corticosteroids have been substantiated by a number of experimental evidences and clinical studies, about 10% of the treated neonates remains affected by RDS. Corticosteroids affect the composition of lung parenchyma, by increasing elastin content and by decreasing alveolo-capillary permeability to serum proteins. Since thyrotropic releasing hormone (TRH) has been shown to potentiate the effects of corticosteroids a combination of the two drugs may be the treatment of choice for prenatal prevention of RDS. Key words: respiratory distress syndrome ticosteroids; lung permeability.
(RDS);
fetal lung; surfactant;
cor-
It is generally recognised that various pharmacologic agents and hormones, including corticosteroid and thyroid hormones, affect fetal lung maturity and surfactant production. The clinical usefulness of corticosteroids in reducing the incidence of RDS (respiratory distress syndrome) in premature infants is well established. However, some instances have been reported (about 10%) where the fetal lung fails to respond to this mode of treatment. This is particularly the case of Caucasian male infants and of twins and after short duration of therapy; moreover, the therapy is limited by the number of women eligible for treatment, because of exclusion criteria and more than 48 h delay of delivery necessary for the therapeutic efficacy of corCorrespondence to: Ermelando V. Cosmi, 2nd Institute of Obstetrics and Gynecology, University ‘La Sapienza’, Cittl Universitaria, 001000 Rome, Italy.
284
ticosteroids. Studies by Ballard [1] have shown that the incidence of RDS is reduced and the survival rate of the newborn infant is increased significantly, if the interval from treatment with corticosteroids to delivery is around 4 but less than 5 days. There is some indication from both human [2,3] and animal [4,5] studies, that the maximal response may be dependent also on gestational age at the time of treatment. In fetal rabbits, the administration of cortisol intraperitoneally (0.1 mg) at 24-27 days gestation increased the pulmonary surfactant pool size, particularly the intracellular pool. Overall, the greatest effect was observed with the treatment on the 24th gestational day [4]. Several in vitro and in vivo studies, both in humans [1,6] and animals [4,7,8], involving a wide range of indices of lung maturity, i.e. biochemical, morphologic, physiologic, have demonstrated additive, or supra-additive, maturational effects from the combined use of various hormones, e.g. thyroid, prolactin and corticosteroid hormones and beta-agonists. In addition, some authors [9-l 1] have reported that the combination of glucocorticoid and thyroid hormones improves the response of the preterm rabbit and human lung to the treatment with exogenous surfactant, thereby reducing both the incidence and the severity of RDS. Synergism of multiple hormones has been described in other organs, particularly the mammary gland, where lactogenesis is stimulated by a group of hormones including cortisol, triiodothyronine (T3) and prolactin. However, the role of prolactin and of estradiol in fetal lung maturity has been a subject of controversy. TRH is an attractive effector of fetal lung maturity because it readily crosses the placenta and causes thyroid axis stimulation and the release of prolactin and estrogen [4]. The level at which glucocorticoid and thyroid hormones exert their control, whether affecting directly the surfactant system of the lung or some other aspects of lung maturity, such as lung structure [9], has not been clarified. Liggins et al. [8] have found a synergistic effect of corticosteroids and thyrotropic releasing hormone (TRH) on the distensibility and the stability of the fetal sheep lung. In our studies in fetal rabbits the administration of corticosteroids to the doe (0.2 mg/kg betamethasone on day 25 and 26 gestation) did not affect saturated phosphatidylcoline lavageable pool in the neonatal lung after delivery at 27 days gestation. Corticosteroids, however, influenced pressure/volume diagram of 27 days’ rabbit lungs from neonates of does treated with betamethasone when compared to that from untreated neonatal lungs [15]. Betamethasone administered with the same modality did not significantly alter collagen/elastin as evidentiated by the concentration of hydroxyproline versus the content of desmosine in total lung. In addition, corticosteroids decreased the protein leak from the vascular space to the airways. This latter effect has been demonstrated to determine albumin concentration in alveolar space of rabbit neonates after IV injection of human albumin in betamethasone treated animals and in controls [ 14,151. Ikegami et al. [9], have reported similar results. In addition they have shown that the combined use of betamethasone and TRH in surfactant-treated preterm fetal rabbits significantly improves lung compliance and augments the response of the preterm lung to exogenous surfactant. Another important issue that needs to be addressed is to identify the minimal effective corticosteroid dose that would influence lung maturation. From experimental studies performed on rabbits, it appears that surfactant dose can be reduced as low
285
as 0.05 &kg, while retaining all beneficial effects on lung maturation [16]. Except for two recent studies by Rooney and Oulton et al. [4], there is little information on whether the response by the fetal lung to TRH alone or in combination with glucocorticoids is dependent on the timing of treatment. Oulton et al. [4] have found that the greatest effect on phospholipid content of intracellular surfactant pool in fetal rabbit lung at 27 days gestation is encountered with a combination of cortisol (0.1 mg given intraperitoneally at 24 days gestation) plus TRH (40 pg/kg per dose IV to the doe at 25,25,26 days gestation), i.e. IO-fold increment over untreated controls. Given its combination, the response to TRH was greatly enhanced by prior exposure to glucocorticoids. Tabor et al. have studied the dose-response effect of TRH (5, 10 or 50 pg/kg every 12 h. for four doses opposed to a single dose of 20 rglkg) when administered in conjunction with betamethasone (0.5 &kg) to pregnant does starting from day 25 of gestation on fetuses delivered on day 27. There were no differences among the four TRH doses in surfactant pool sizes, compliances or protein leak into or out of the airspaces, while the groups that received multiple doses had a higher perinatal loss rate than single dose groups. The addition of TRH to betamethasone significantly decreased lung permeability with respect to betamethasone alone, with an effect which was apparent even after surfactant administration. The authors question the need for multiple doses of TRH in the light of a higher perinatal mortality rate and the theoretical long term effects of fetal hyperthyroidism. In conclusion, glucocorticoids and TRH alone improve many of the measurements used to assesspulmonary maturation; the combination of the two exerts a greater effect and, in addition, improves the response of the lung to exogenous surfactant. Possibly the most effective therapy for RDS is the combined use of agents such as corticosteroids and TRH (given at the lowest doses shown to be effective) given prenatally together with a surfactant treatment after birth. This work was supported by CNR and MURST, Italy. References 1 Ballard, F.L. (1984): Combined hormonal treatment and lung maturation. Semin. Perinatol., 8,283. 2 Collaborative Group on Antenatl Steroid Therapy. (1981): Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am. J. Obstet. Gynecol., 141, 276. 3 Doran, T.A., Swyer, B. and McMurray, B. (1980): Results of a double-blind controlled study on the use of betamethasone in the prevention of respiratory distress syndrome. Am. J. Obstet. Gynecol., 136, 313. 4 O&on, M., Rasmussen, M.G., Yoon, R.Y. and Frazer, M. (1989): Gestation-dependent effects of the combined treatment of glucocorticoids and thyrotropin-releasing hormone on surfactant production by fetal rabbit lung. Am. J. Obstet. Gynecol., 160, 961. 5 Taeusch, H.W., Brown, E., Torday, J.S. and Nielsen, H.C. (1981): Magnitude and duration of lung response to dexamethasone in fetal sheep. Am. J. Obstet. Gynecol., 140, 452. 6 Gonzales, L.W., Ballard, F.L., Ertsey, R. and Williams, M.C. (1987): Glucocorticoids and thyroid hormones stimulate biochemical and morphological differentiation of human fetal lung in organ culture. J. Clin. Endocr. Metab., 62, 678. 7 Gross, I., Dynia, D.W., Wilson, C.M., Ingleson, L.D., Gewolb, I.H. and Rooney, S.A. (1984): Glucocorticoid-thyroid hormone interactions in fetal rat lung. Pediatr. Res., 18, 191. 8 Liggins, G.C., Schellenberg, J.C., Manzai, M., Kitterman J.A. and Lee, C.H. (1988): Synergism of
286
9 IO II 12 13 14
15 16 17
cortisol and thyrotropin-releasing hormone in lung maturation in fetal sheep. J. Appl. Physioi. 65. 1988. Ikegami, M., Jobe, A.N., Pettenazzo, A., Sidner, S.R., Berry D.D. and RufIini, L. (1987): Effects of maternal treatment with corticosteroids, Ts, TRH and their combination on lung function of ventilated preterm rabbits with and without surfactant treatment. Am. Rev. Respir. Dis., 892, 136. Warburton, D., Parton, L., Buckley, S., Cosico, L., Enns, G. and Saluna, T. (1988): Combined effects of corticosteroid, thyroid hormones, and beta-agonists on surfactant, pulmonary mechanics. and beta-receptor binding in fetal lamb lung. Pediatr. Res., 24, 166. Farrell, E.E., Silver, R.K., Kimberlin, L.V., Wolf, ES. and Dusik, J.M. (1989): Impact of antenatal dexamethasone administration on respiratory distress syndrome in surfactant-treated infants. Am. J. Obstet. Gynecol., 161, 628. Anceschi, M.M., Petrelli, A., Zaccardo, G., Barbati, A., Di Renzo, G.C., Cosmi, E.V. and Hallman, M. (1988): Inositol and glucocorticoid in the development of lung stability in male and female rabbit fetuses. Pediatr. Res., 24, 617. Anceschi, M.M., Palmerini, CA., Guida, E., Guida, E., Broccucci, K., Luzi, P. and Cosmi, E.V. (1990): Fetal rabbit lung collagen and elastin: ontogeny and effects of steroids. Pediatr. Res., 27, 25A. Anceschi, M.M., Roberston, B., Broccucci, L., Barbati, A., Zaccardo, G. and Cosmi, E.V. (1990): Immunochemical and immunohistochemical evaluation of lung permeability in ventilated newborn rabbits. Exp. Lung Res., 16, 593. Cosmi, E.V. (1991): New forntiers in prenatal prevention of RDS J. Perin. Med., 19, 170s. Tabor, B.L., Ikegami, M., Jobe, A.H., Yamada, T., Oetomo, S.B. (1990): Dose response of thyrotropin-releasing hormone on polmonary maturation in corticosteroid-treated preterm rabbits. Am. J. Obstet. Gynecol., 163, 669. Tabor, B.L., Ryder, E.D., Ikegami, M. and Lewis, J.F. (1991): Doe effect of antenatal corticosteroids for induction of lung maturation in preterm rabbits. Am. J. Obstet. Gynecol., 164, 675.
Human
Development,
29 (1992)
283
283-286
Elsevier Scientific Publishers Ireland Ltd. EHD 01289
Prenatal prevention of respiratory distress syndrome: new pharmacologic approaches Ermelando V. Cosmi 2nd Institute
of Obstetrics
and Gynecology,
University
‘La Sapienza’,
Rome
(Italy)
Summary
A deficit of lung surfactant is known to be involved in the pathophysiology of the respiratory distress syndrome of the neonate (RDS), which is still responsible of about one fourth of total neonatal mortality. It has been well documented that maternal administration of corticosteroids enhances fetal lung maturity, promoting synthesis of surfactants and altering also the structure of the lung parenchyma. Although the beneficial effects of corticosteroids have been substantiated by a number of experimental evidences and clinical studies, about 10% of the treated neonates remains affected by RDS. Corticosteroids affect the composition of lung parenchyma, by increasing elastin content and by decreasing alveolo-capillary permeability to serum proteins. Since thyrotropic releasing hormone (TRH) has been shown to potentiate the effects of corticosteroids a combination of the two drugs may be the treatment of choice for prenatal prevention of RDS. Key words: respiratory distress syndrome ticosteroids; lung permeability.
(RDS);
fetal lung; surfactant;
cor-
It is generally recognised that various pharmacologic agents and hormones, including corticosteroid and thyroid hormones, affect fetal lung maturity and surfactant production. The clinical usefulness of corticosteroids in reducing the incidence of RDS (respiratory distress syndrome) in premature infants is well established. However, some instances have been reported (about 10%) where the fetal lung fails to respond to this mode of treatment. This is particularly the case of Caucasian male infants and of twins and after short duration of therapy; moreover, the therapy is limited by the number of women eligible for treatment, because of exclusion criteria and more than 48 h delay of delivery necessary for the therapeutic efficacy of corCorrespondence to: Ermelando V. Cosmi, 2nd Institute of Obstetrics and Gynecology, University ‘La Sapienza’, Cittl Universitaria, 001000 Rome, Italy.
284
ticosteroids. Studies by Ballard [1] have shown that the incidence of RDS is reduced and the survival rate of the newborn infant is increased significantly, if the interval from treatment with corticosteroids to delivery is around 4 but less than 5 days. There is some indication from both human [2,3] and animal [4,5] studies, that the maximal response may be dependent also on gestational age at the time of treatment. In fetal rabbits, the administration of cortisol intraperitoneally (0.1 mg) at 24-27 days gestation increased the pulmonary surfactant pool size, particularly the intracellular pool. Overall, the greatest effect was observed with the treatment on the 24th gestational day [4]. Several in vitro and in vivo studies, both in humans [1,6] and animals [4,7,8], involving a wide range of indices of lung maturity, i.e. biochemical, morphologic, physiologic, have demonstrated additive, or supra-additive, maturational effects from the combined use of various hormones, e.g. thyroid, prolactin and corticosteroid hormones and beta-agonists. In addition, some authors [9-l 1] have reported that the combination of glucocorticoid and thyroid hormones improves the response of the preterm rabbit and human lung to the treatment with exogenous surfactant, thereby reducing both the incidence and the severity of RDS. Synergism of multiple hormones has been described in other organs, particularly the mammary gland, where lactogenesis is stimulated by a group of hormones including cortisol, triiodothyronine (T3) and prolactin. However, the role of prolactin and of estradiol in fetal lung maturity has been a subject of controversy. TRH is an attractive effector of fetal lung maturity because it readily crosses the placenta and causes thyroid axis stimulation and the release of prolactin and estrogen [4]. The level at which glucocorticoid and thyroid hormones exert their control, whether affecting directly the surfactant system of the lung or some other aspects of lung maturity, such as lung structure [9], has not been clarified. Liggins et al. [8] have found a synergistic effect of corticosteroids and thyrotropic releasing hormone (TRH) on the distensibility and the stability of the fetal sheep lung. In our studies in fetal rabbits the administration of corticosteroids to the doe (0.2 mg/kg betamethasone on day 25 and 26 gestation) did not affect saturated phosphatidylcoline lavageable pool in the neonatal lung after delivery at 27 days gestation. Corticosteroids, however, influenced pressure/volume diagram of 27 days’ rabbit lungs from neonates of does treated with betamethasone when compared to that from untreated neonatal lungs [15]. Betamethasone administered with the same modality did not significantly alter collagen/elastin as evidentiated by the concentration of hydroxyproline versus the content of desmosine in total lung. In addition, corticosteroids decreased the protein leak from the vascular space to the airways. This latter effect has been demonstrated to determine albumin concentration in alveolar space of rabbit neonates after IV injection of human albumin in betamethasone treated animals and in controls [ 14,151. Ikegami et al. [9], have reported similar results. In addition they have shown that the combined use of betamethasone and TRH in surfactant-treated preterm fetal rabbits significantly improves lung compliance and augments the response of the preterm lung to exogenous surfactant. Another important issue that needs to be addressed is to identify the minimal effective corticosteroid dose that would influence lung maturation. From experimental studies performed on rabbits, it appears that surfactant dose can be reduced as low
285
as 0.05 &kg, while retaining all beneficial effects on lung maturation [16]. Except for two recent studies by Rooney and Oulton et al. [4], there is little information on whether the response by the fetal lung to TRH alone or in combination with glucocorticoids is dependent on the timing of treatment. Oulton et al. [4] have found that the greatest effect on phospholipid content of intracellular surfactant pool in fetal rabbit lung at 27 days gestation is encountered with a combination of cortisol (0.1 mg given intraperitoneally at 24 days gestation) plus TRH (40 pg/kg per dose IV to the doe at 25,25,26 days gestation), i.e. IO-fold increment over untreated controls. Given its combination, the response to TRH was greatly enhanced by prior exposure to glucocorticoids. Tabor et al. have studied the dose-response effect of TRH (5, 10 or 50 pg/kg every 12 h. for four doses opposed to a single dose of 20 rglkg) when administered in conjunction with betamethasone (0.5 &kg) to pregnant does starting from day 25 of gestation on fetuses delivered on day 27. There were no differences among the four TRH doses in surfactant pool sizes, compliances or protein leak into or out of the airspaces, while the groups that received multiple doses had a higher perinatal loss rate than single dose groups. The addition of TRH to betamethasone significantly decreased lung permeability with respect to betamethasone alone, with an effect which was apparent even after surfactant administration. The authors question the need for multiple doses of TRH in the light of a higher perinatal mortality rate and the theoretical long term effects of fetal hyperthyroidism. In conclusion, glucocorticoids and TRH alone improve many of the measurements used to assesspulmonary maturation; the combination of the two exerts a greater effect and, in addition, improves the response of the lung to exogenous surfactant. Possibly the most effective therapy for RDS is the combined use of agents such as corticosteroids and TRH (given at the lowest doses shown to be effective) given prenatally together with a surfactant treatment after birth. This work was supported by CNR and MURST, Italy. References 1 Ballard, F.L. (1984): Combined hormonal treatment and lung maturation. Semin. Perinatol., 8,283. 2 Collaborative Group on Antenatl Steroid Therapy. (1981): Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am. J. Obstet. Gynecol., 141, 276. 3 Doran, T.A., Swyer, B. and McMurray, B. (1980): Results of a double-blind controlled study on the use of betamethasone in the prevention of respiratory distress syndrome. Am. J. Obstet. Gynecol., 136, 313. 4 O&on, M., Rasmussen, M.G., Yoon, R.Y. and Frazer, M. (1989): Gestation-dependent effects of the combined treatment of glucocorticoids and thyrotropin-releasing hormone on surfactant production by fetal rabbit lung. Am. J. Obstet. Gynecol., 160, 961. 5 Taeusch, H.W., Brown, E., Torday, J.S. and Nielsen, H.C. (1981): Magnitude and duration of lung response to dexamethasone in fetal sheep. Am. J. Obstet. Gynecol., 140, 452. 6 Gonzales, L.W., Ballard, F.L., Ertsey, R. and Williams, M.C. (1987): Glucocorticoids and thyroid hormones stimulate biochemical and morphological differentiation of human fetal lung in organ culture. J. Clin. Endocr. Metab., 62, 678. 7 Gross, I., Dynia, D.W., Wilson, C.M., Ingleson, L.D., Gewolb, I.H. and Rooney, S.A. (1984): Glucocorticoid-thyroid hormone interactions in fetal rat lung. Pediatr. Res., 18, 191. 8 Liggins, G.C., Schellenberg, J.C., Manzai, M., Kitterman J.A. and Lee, C.H. (1988): Synergism of
286
9 IO II 12 13 14
15 16 17
cortisol and thyrotropin-releasing hormone in lung maturation in fetal sheep. J. Appl. Physioi. 65. 1988. Ikegami, M., Jobe, A.N., Pettenazzo, A., Sidner, S.R., Berry D.D. and RufIini, L. (1987): Effects of maternal treatment with corticosteroids, Ts, TRH and their combination on lung function of ventilated preterm rabbits with and without surfactant treatment. Am. Rev. Respir. Dis., 892, 136. Warburton, D., Parton, L., Buckley, S., Cosico, L., Enns, G. and Saluna, T. (1988): Combined effects of corticosteroid, thyroid hormones, and beta-agonists on surfactant, pulmonary mechanics. and beta-receptor binding in fetal lamb lung. Pediatr. Res., 24, 166. Farrell, E.E., Silver, R.K., Kimberlin, L.V., Wolf, ES. and Dusik, J.M. (1989): Impact of antenatal dexamethasone administration on respiratory distress syndrome in surfactant-treated infants. Am. J. Obstet. Gynecol., 161, 628. Anceschi, M.M., Petrelli, A., Zaccardo, G., Barbati, A., Di Renzo, G.C., Cosmi, E.V. and Hallman, M. (1988): Inositol and glucocorticoid in the development of lung stability in male and female rabbit fetuses. Pediatr. Res., 24, 617. Anceschi, M.M., Palmerini, CA., Guida, E., Guida, E., Broccucci, K., Luzi, P. and Cosmi, E.V. (1990): Fetal rabbit lung collagen and elastin: ontogeny and effects of steroids. Pediatr. Res., 27, 25A. Anceschi, M.M., Roberston, B., Broccucci, L., Barbati, A., Zaccardo, G. and Cosmi, E.V. (1990): Immunochemical and immunohistochemical evaluation of lung permeability in ventilated newborn rabbits. Exp. Lung Res., 16, 593. Cosmi, E.V. (1991): New forntiers in prenatal prevention of RDS J. Perin. Med., 19, 170s. Tabor, B.L., Ikegami, M., Jobe, A.H., Yamada, T., Oetomo, S.B. (1990): Dose response of thyrotropin-releasing hormone on polmonary maturation in corticosteroid-treated preterm rabbits. Am. J. Obstet. Gynecol., 163, 669. Tabor, B.L., Ryder, E.D., Ikegami, M. and Lewis, J.F. (1991): Doe effect of antenatal corticosteroids for induction of lung maturation in preterm rabbits. Am. J. Obstet. Gynecol., 164, 675.
