Lung (1990) Suppl:864-869 @ Springer-Verlag
New York Inc. 1990
A Multicenter Randomized Controlled Clinical Trial of Bovine Surfactant for Prevention of Respiratory Distress Syndrome L. Gortner, 1 U. Bernsau, H. H. Hellwege, G. Hieronimi, G. Jorch, and H. L. Reiter z University Children's Hospital, Ulm, Federal Republic of Germany
Abstract. Treatment with bovine surfactant (SF-RI 1) was shown to be efficacious in improving pulmonary function and in increasing survival rate without BPD in very premature infants. Surfactant therapy did not affect the risk of major complications of prematurity.
Key words: Respiratory distress syndrome--Bovine surfactantwPremature infantswPulmonary function. Introduction
Since the beginning of the 1980s, treatment of respiratory distress syndrome (RDS) with natural surfactant in premature infants has become reality. Either human [1, 2], bovine [3-8] or porcine surfactants [9] have been used for prophylaxis or treatment of established RDS. During the first 24-48 hours after surfactant, an improvement in gas exchange demonstrated by lower respirator settings was shown for all surfactant preparations and increased survival rate without bronchopulmonary dysplasia (BPD) was observed in part of the studies [10]. After demonstration of the efficacy of a new bovine surfactant (SF-RI 1) in premature rabbits [11] and lambs [12], this particular surfactant preparation was used in a clinical pilot study. Improvement in lung function could be demonstrated in very low birth weight infants suffering from RDS [13]. We thereafter started a multicenter controlled clinical trial on the effects o f bovine surfactant (SF-RI 1) in very premature infants (gestational age, GA, 25-30 weeks) for prevention of RDS.
Offprint requests to: Dr. L. Gortner, Universit/its-Kinderklinik, D-7900, Ulm, FRG.
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Bovine Surfactant for RIDS
Table 1. Clinical data of very premature surfactant-treated and control infants
Gestational age* (weeks) Birth weight* (g) Sex ratio (male/female) Mode of delivery (vaginal/ces. section) Apgar at 5 minutes -5 Umbilical* artery pH at birth *
Surfactant group (N = 34)
Control group (N = 35)
28.0 --- 1.5 1,048 - 299 15/19 9/25 1/33 7.27 ± 0.11
27.6 ± 1.5 969 ± 269 16/I9 4/31 3/32 7.24 ± 0.13
Means --+ SD
Patients and Methods During the study period, from September 1987 through May 1988, infants of 25-30 weeks GA born at the participating centers were enrolled in this study after parental, informed, written consent. Further criteria were: initiation of mechanical ventilation and surfactant application during the first hour after birth, sterile cultures of blood and tracheal aspirate at birth and absence of major malformations. The surfactant preparation (50 mg/kg birth weight, b.w.) was applicated through a feeding tube, the tip of which was positioned at the distal end of the e.t.-tube in infants randomized for treatment, whereas air was given intratracheally to control infants. Mechanical ventilation was standardized for the first days with inspiratory times of 0.2-0.25 seconds, the positive end-expiratory pressure was +3 cm H,.O, given fraction of inspired oxygen (FiOz) was 0.5 or peak inspirato~ pressures (PIP) >22 cm H20 in infants of 25 cm H20 in infants of 750-1,000 b. w. and >28 cm HzO in infants of 1,000-1,500 g b. w. Respirator settings were adapted in order to maintain the PaO2 between 50 to 70 mm Hg, the PaCO2 between 40 to 45 mmHg. The primary outcome was categorized as survival without bronchopulmonary dysplasia (BPD). BPD was defined as either ventilator dependency or, in case of spontaneous respiration, as FiO2 >0.3 in order to maintain the PaO2 > 50 mmHg at day 28 of life according to the criteria proposed by Toce et al. [14]. The statistical design was a sequential analysis, type I and type II error 5% each.
Results N o d i f f e r e n c e s in t h e i n c i d e n c e o f p r e n a t a l s t e r o i d a n d f i z - a g o n i s t t h e r a p y c o u l d be demonstrated between surfactant and control infants. Table 1 shows the clinical data of the very premature infants. Both groups w e r e q u i t e c o m p a r a b l e w i t h r e s p e c t to c l i n i c a l c h a r a c t e r i s t i c s . S h o r t - t e r m eff e c t s o f s u r f a c t a n t t r e a t m e n t w e r e a n i m p r o v e m e n t in o x y g e n a t i o n a n d a d e c r e a s e in p e a k i n s p i r a t o r y a n d m e a n a i r w a y p r e s s u r e s ( F i g s . 1, 2). O n e d o s e o f s u r f a c t a n t w a s g i v e n to 24 i n f a n t s , 4 i n f a n t s r e c e i v e d 2 d o s e s , 6 i n f a n t s 4 d o s e s . The survival rate without bronchopulmonary d y s p l a s i a w a s 7 6 % (26/34) in s u r f a c t a n t a n d 4 0 % (14/35) in c o n t r o l i n f a n t s . T h i s d i f f e r e n c e is s t a t i s t i c a l l y
L. Gortner et at.
866 FiO 2
A
o,9
0.5
0,1
l
12
24
48
72
96
pa/pAO 2
120
B
0.5
0,3
i l/.
i
0.1
12
24
48
72
i
96
120
Fig. 1. FiO2 (A) and pa/AO2 (B) values in surfactant-treated (open bars) and control (closed bars) infants. Values are given as mean +-- SE. Time is given in hours after the first surfactant application.
Hours after bovine surfactant
PIP (cm H20)
A
24.0 22.0 20,0 16,0 16,0 14.0 12
24
48
72
96
MAP (mm Hg)
120
S
9,0 70
3.0
1,0
.
I
12
24
48
72
Hours after bovine surfactant
96
Fig. 2. PIP (A, cm H20) and MAP (B, mmHg) values in surfactant-treated and control infants. Symbols, statistics, and times as in Fig. 1. 120
Bovine Surfactant for RDS
867
Table 2. Pulmonary and extrapulmonary complications in surfactant-treated and control infants
Pulmonary interstitial emphysema Pneumothorax Pneumomediastinum Intracranial hemorrhage Grade* I Grade II Grade III Necrotizing enterocolitis Nosocomial infections Sepsis Pneumonia *
Surfactant group (N = 34)
Control group (N = 35)
4 (12%) 3 (9%) 0 12 (35%) 5 2 1 1 (3%)
6 (17%) 4 (11%) 1 (3%) 11 (31%) 7 2 2 1 (3%)
8 (24%) 9 (27%)
7 (20%) 13 (37%)
Grading according to Shankaran et al. [17]
significant (p = 0.003, sequential analysis). T h e overall survival rate was 82% (28/34) in surfactant and 69% (24/35) in control infants. The m e a n total time of mechanical ventilation in survivors was 11 days in surfactant and 27 days in controls, total time of hospital care 81 days in surfactant and 107 days in control infants. P u l m o n a r y and extrapulmonary complications during the first 28 days are given in Table 2. N o differences were o b s e r v e d b e t w e e n both groups with r e s p e c t to short-term complications of prematurityo
Discussion Controlled clinical trials of natural surfactant preparations in p r e m a t u r e infants with RDS have demonstrated beneficial effects either after prophylactic or therapeutic intratracheal application. D e c r e a s e d oxygen requirements and ventilator pressures were demonstrated in all studies as a short-term consequence o f surfactant treatment [10]. T h e s e results were confirmed in the present study. In contrast to other clinical studies, we were unable to d e m o n s t r a t e differences i n the incidence of pulmonary air leak s y n d r o m e s (i.e., p u l m o n a r y interstitial e m p h y s e m a , pneumothorax) b e t w e e n surfactant and control infants. This fact m a y be explained in part by mechanical ventilation using short inspiratory times (0.2 to 0.25 seconds resulting in respiratory rates of 70-80/min), which is in contrast to m o s t other published controlled clinical trials on natural surfacrant. The incidence of pulmonary air leak s y n d r o m e s in surfactant treated infants was 12% in our study, which is within the range reported by other groups. The incidence of pulmonary air leak s y n d r o m e s in our control group (17%) is m u c h lower than the incidence reported by other groups [15]. It could be d e m o n s t r a t e d previously, that ventilation at rapid rates (60/min) using short
868
L. Gortner et al.
inspiratory times reduces the incidence of pulmonary air leak syndromes compared to a respiratory rate of 30/min using inspiratory times of 0.5-1 s [16]. As in most controlled clinical trials with natural surfactant, premature infants were ventilated at respiratory rates of 30-50/min, our control infants might have profited from the mechanical ventilation at rapid rates with respect to the incidence of pulmonary air leak syndromes. The incidence of extrapulmonary complications of prematurity (i.e., intracranial hemorrhage, patent ductus arteriousus and necrotizing enterocolitis) was in the same range for both treatment groups and showed no principal differences compared to other studies.
References 1. Hallman M, Merritt TA, Jarvenpaa AL, Boynton B, Mannino F, Gluck L, Moore T, Edwards D (1985) Exogenous human surfactant for treatment of severe respiratory distress syndrome: a randomized prospective clinical trial. J Pediatr 106:963-969 2. Merritt TA, Hallman M, Bloom BT, Berry C, Benirschke K, Sahn D, Key T, Edwards D, Jarvenpaa AL, Pohjavuori M, Kankaanpaa K, Kunnas M, Paatero H, Rapola J, Jaaskelainen J (1986) Prophylactic treatment of very premature infants with human surfactant. N Engl J Med 315:785-790 3. Enhorning G, Shennan A, Possmayer F, Dunn M, Chen CP, Milligan J (1985) Prevention of neonatal respiratory distress syndrome by tracheal installation of surfactant: a randomized clinical trial. Pediatrics 76:145-153 4. Kwong MS, Egan EA, Notter RH, Shapiro DL (1985) Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 76:585-592 5. Gitlin JD, Soil RF, Parad RB, Horbar JD, Feldmann HA, Lucey JF, Taeusch HW (1987) Randomized controlled trial of exogenous surfactant for the treatment of hyaline membrane disease. Pediatrics 79:31-37 6. Raju TNK, Vidyasagar D, Bhat R, Sobel D, McCulloch KM, Anderson M, Maeta H, Levy PS, Furner S (1987) Double-blind controlled trial of single-dose treatment with bovine surfactant in severe hyaline membrane disease. Lancet I:651-656 7. Kendig JW, Notter RH, Cox C, Aschner JL, Benn S, Bernstein RM, Hendricks-Munoz K, Maniscalco WM, Metlay LA, Phelps DL, Sinkin RA, Wood BP, Shapiro DL (1988) Surfactant replacement therapy at birth: Final analysis of a clinical trial and comparisons with similar trials. Pediatrics 82:756-762 8. Horbar JD, Soil RF, Sutherland JM, Kotagal U, Philip AGS, Kessler DL, Little GA, Edwards WH, Vidyasagar D, Raju TNK, Jobe AH, Ikegami M, Mullett MD, Myerberg DZ, McAufliffe TL, Lucey JF (1989) A multicenter randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome. N Engl J Med 320:959-965 9. Collaborative European Multicenter Study Group (1988) Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial. Pediatrics 82:683-691 10. Merritt TA, Hallman M (1988) Surfactant replacement. A new era with many challenges for neonatal medicine. Am J Dis Child 142:1333-1339 11. Disse B, Gortner L, Weller E, Eberhardt H, Ziegler H (1988) Efficacy and standardisation of SF-RI 1: a preparation from bovine lung suffactant. In: Lachmann B, ed. Surfactant replacement therapy in neonatal and adult respiratory distress syndrome. Berlin, Heidelberg, New York: Springer-Verlag, pp 37-41 12. Gortner L, Pohlandt F, Disse B, Weller E (in press) Effects of tracheal instillation of bovine surfactant (SF-RI 1) in premature lambs. Eur J Pediatr 13. Gortner L, Pohlandt F, Bartmann P, Disse B (1990) Die Behandlung des Atemnotsyndroms (RDS) sehr kleiner FrCthgeborener mit nattirlichem Surfactant. Monatsschr Kinderheilk 138: 8-12
Bovine Surfactant for RDS
869
14. Toce SS, Farrell PM, Leavitt LA, Samuels DP, Edwards DK (1984) Clinical and roentgenographic scoring systems for assessing bronchopulmonary dysplasia. Am J Dis Child 138:58t585 15. Jobe A, Ikegami M (1987) Surfactant for the treatment of respiratory distress syndrome. Am Rev Respir Dis 136:1256-1275 16. Heicher DA, Kasting DS, Harrod JR (1981) Prospective clinical comparison of two methods for mechanical ventilation of neonates. Rapid rate and short inspiratory time versus slow rate and long inspiratory time. J Pediatr 98:957-961 17. Shankaran S, Slovis TL, Bedard MP, Poland RL (1982) Sonographic classification of intracranial hemorrhage. A prognostic indicator of mortality, morbidity, and short-term neurologic outcome. J Pediatr 100:469-475
New York Inc. 1990
A Multicenter Randomized Controlled Clinical Trial of Bovine Surfactant for Prevention of Respiratory Distress Syndrome L. Gortner, 1 U. Bernsau, H. H. Hellwege, G. Hieronimi, G. Jorch, and H. L. Reiter z University Children's Hospital, Ulm, Federal Republic of Germany
Abstract. Treatment with bovine surfactant (SF-RI 1) was shown to be efficacious in improving pulmonary function and in increasing survival rate without BPD in very premature infants. Surfactant therapy did not affect the risk of major complications of prematurity.
Key words: Respiratory distress syndrome--Bovine surfactantwPremature infantswPulmonary function. Introduction
Since the beginning of the 1980s, treatment of respiratory distress syndrome (RDS) with natural surfactant in premature infants has become reality. Either human [1, 2], bovine [3-8] or porcine surfactants [9] have been used for prophylaxis or treatment of established RDS. During the first 24-48 hours after surfactant, an improvement in gas exchange demonstrated by lower respirator settings was shown for all surfactant preparations and increased survival rate without bronchopulmonary dysplasia (BPD) was observed in part of the studies [10]. After demonstration of the efficacy of a new bovine surfactant (SF-RI 1) in premature rabbits [11] and lambs [12], this particular surfactant preparation was used in a clinical pilot study. Improvement in lung function could be demonstrated in very low birth weight infants suffering from RDS [13]. We thereafter started a multicenter controlled clinical trial on the effects o f bovine surfactant (SF-RI 1) in very premature infants (gestational age, GA, 25-30 weeks) for prevention of RDS.
Offprint requests to: Dr. L. Gortner, Universit/its-Kinderklinik, D-7900, Ulm, FRG.
865
Bovine Surfactant for RIDS
Table 1. Clinical data of very premature surfactant-treated and control infants
Gestational age* (weeks) Birth weight* (g) Sex ratio (male/female) Mode of delivery (vaginal/ces. section) Apgar at 5 minutes -5 Umbilical* artery pH at birth *
Surfactant group (N = 34)
Control group (N = 35)
28.0 --- 1.5 1,048 - 299 15/19 9/25 1/33 7.27 ± 0.11
27.6 ± 1.5 969 ± 269 16/I9 4/31 3/32 7.24 ± 0.13
Means --+ SD
Patients and Methods During the study period, from September 1987 through May 1988, infants of 25-30 weeks GA born at the participating centers were enrolled in this study after parental, informed, written consent. Further criteria were: initiation of mechanical ventilation and surfactant application during the first hour after birth, sterile cultures of blood and tracheal aspirate at birth and absence of major malformations. The surfactant preparation (50 mg/kg birth weight, b.w.) was applicated through a feeding tube, the tip of which was positioned at the distal end of the e.t.-tube in infants randomized for treatment, whereas air was given intratracheally to control infants. Mechanical ventilation was standardized for the first days with inspiratory times of 0.2-0.25 seconds, the positive end-expiratory pressure was +3 cm H,.O, given fraction of inspired oxygen (FiOz) was 0.5 or peak inspirato~ pressures (PIP) >22 cm H20 in infants of 25 cm H20 in infants of 750-1,000 b. w. and >28 cm HzO in infants of 1,000-1,500 g b. w. Respirator settings were adapted in order to maintain the PaO2 between 50 to 70 mm Hg, the PaCO2 between 40 to 45 mmHg. The primary outcome was categorized as survival without bronchopulmonary dysplasia (BPD). BPD was defined as either ventilator dependency or, in case of spontaneous respiration, as FiO2 >0.3 in order to maintain the PaO2 > 50 mmHg at day 28 of life according to the criteria proposed by Toce et al. [14]. The statistical design was a sequential analysis, type I and type II error 5% each.
Results N o d i f f e r e n c e s in t h e i n c i d e n c e o f p r e n a t a l s t e r o i d a n d f i z - a g o n i s t t h e r a p y c o u l d be demonstrated between surfactant and control infants. Table 1 shows the clinical data of the very premature infants. Both groups w e r e q u i t e c o m p a r a b l e w i t h r e s p e c t to c l i n i c a l c h a r a c t e r i s t i c s . S h o r t - t e r m eff e c t s o f s u r f a c t a n t t r e a t m e n t w e r e a n i m p r o v e m e n t in o x y g e n a t i o n a n d a d e c r e a s e in p e a k i n s p i r a t o r y a n d m e a n a i r w a y p r e s s u r e s ( F i g s . 1, 2). O n e d o s e o f s u r f a c t a n t w a s g i v e n to 24 i n f a n t s , 4 i n f a n t s r e c e i v e d 2 d o s e s , 6 i n f a n t s 4 d o s e s . The survival rate without bronchopulmonary d y s p l a s i a w a s 7 6 % (26/34) in s u r f a c t a n t a n d 4 0 % (14/35) in c o n t r o l i n f a n t s . T h i s d i f f e r e n c e is s t a t i s t i c a l l y
L. Gortner et at.
866 FiO 2
A
o,9
0.5
0,1
l
12
24
48
72
96
pa/pAO 2
120
B
0.5
0,3
i l/.
i
0.1
12
24
48
72
i
96
120
Fig. 1. FiO2 (A) and pa/AO2 (B) values in surfactant-treated (open bars) and control (closed bars) infants. Values are given as mean +-- SE. Time is given in hours after the first surfactant application.
Hours after bovine surfactant
PIP (cm H20)
A
24.0 22.0 20,0 16,0 16,0 14.0 12
24
48
72
96
MAP (mm Hg)
120
S
9,0 70
3.0
1,0
.
I
12
24
48
72
Hours after bovine surfactant
96
Fig. 2. PIP (A, cm H20) and MAP (B, mmHg) values in surfactant-treated and control infants. Symbols, statistics, and times as in Fig. 1. 120
Bovine Surfactant for RDS
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Table 2. Pulmonary and extrapulmonary complications in surfactant-treated and control infants
Pulmonary interstitial emphysema Pneumothorax Pneumomediastinum Intracranial hemorrhage Grade* I Grade II Grade III Necrotizing enterocolitis Nosocomial infections Sepsis Pneumonia *
Surfactant group (N = 34)
Control group (N = 35)
4 (12%) 3 (9%) 0 12 (35%) 5 2 1 1 (3%)
6 (17%) 4 (11%) 1 (3%) 11 (31%) 7 2 2 1 (3%)
8 (24%) 9 (27%)
7 (20%) 13 (37%)
Grading according to Shankaran et al. [17]
significant (p = 0.003, sequential analysis). T h e overall survival rate was 82% (28/34) in surfactant and 69% (24/35) in control infants. The m e a n total time of mechanical ventilation in survivors was 11 days in surfactant and 27 days in controls, total time of hospital care 81 days in surfactant and 107 days in control infants. P u l m o n a r y and extrapulmonary complications during the first 28 days are given in Table 2. N o differences were o b s e r v e d b e t w e e n both groups with r e s p e c t to short-term complications of prematurityo
Discussion Controlled clinical trials of natural surfactant preparations in p r e m a t u r e infants with RDS have demonstrated beneficial effects either after prophylactic or therapeutic intratracheal application. D e c r e a s e d oxygen requirements and ventilator pressures were demonstrated in all studies as a short-term consequence o f surfactant treatment [10]. T h e s e results were confirmed in the present study. In contrast to other clinical studies, we were unable to d e m o n s t r a t e differences i n the incidence of pulmonary air leak s y n d r o m e s (i.e., p u l m o n a r y interstitial e m p h y s e m a , pneumothorax) b e t w e e n surfactant and control infants. This fact m a y be explained in part by mechanical ventilation using short inspiratory times (0.2 to 0.25 seconds resulting in respiratory rates of 70-80/min), which is in contrast to m o s t other published controlled clinical trials on natural surfacrant. The incidence of pulmonary air leak s y n d r o m e s in surfactant treated infants was 12% in our study, which is within the range reported by other groups. The incidence of pulmonary air leak s y n d r o m e s in our control group (17%) is m u c h lower than the incidence reported by other groups [15]. It could be d e m o n s t r a t e d previously, that ventilation at rapid rates (60/min) using short
868
L. Gortner et al.
inspiratory times reduces the incidence of pulmonary air leak syndromes compared to a respiratory rate of 30/min using inspiratory times of 0.5-1 s [16]. As in most controlled clinical trials with natural surfactant, premature infants were ventilated at respiratory rates of 30-50/min, our control infants might have profited from the mechanical ventilation at rapid rates with respect to the incidence of pulmonary air leak syndromes. The incidence of extrapulmonary complications of prematurity (i.e., intracranial hemorrhage, patent ductus arteriousus and necrotizing enterocolitis) was in the same range for both treatment groups and showed no principal differences compared to other studies.
References 1. Hallman M, Merritt TA, Jarvenpaa AL, Boynton B, Mannino F, Gluck L, Moore T, Edwards D (1985) Exogenous human surfactant for treatment of severe respiratory distress syndrome: a randomized prospective clinical trial. J Pediatr 106:963-969 2. Merritt TA, Hallman M, Bloom BT, Berry C, Benirschke K, Sahn D, Key T, Edwards D, Jarvenpaa AL, Pohjavuori M, Kankaanpaa K, Kunnas M, Paatero H, Rapola J, Jaaskelainen J (1986) Prophylactic treatment of very premature infants with human surfactant. N Engl J Med 315:785-790 3. Enhorning G, Shennan A, Possmayer F, Dunn M, Chen CP, Milligan J (1985) Prevention of neonatal respiratory distress syndrome by tracheal installation of surfactant: a randomized clinical trial. Pediatrics 76:145-153 4. Kwong MS, Egan EA, Notter RH, Shapiro DL (1985) Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 76:585-592 5. Gitlin JD, Soil RF, Parad RB, Horbar JD, Feldmann HA, Lucey JF, Taeusch HW (1987) Randomized controlled trial of exogenous surfactant for the treatment of hyaline membrane disease. Pediatrics 79:31-37 6. Raju TNK, Vidyasagar D, Bhat R, Sobel D, McCulloch KM, Anderson M, Maeta H, Levy PS, Furner S (1987) Double-blind controlled trial of single-dose treatment with bovine surfactant in severe hyaline membrane disease. Lancet I:651-656 7. Kendig JW, Notter RH, Cox C, Aschner JL, Benn S, Bernstein RM, Hendricks-Munoz K, Maniscalco WM, Metlay LA, Phelps DL, Sinkin RA, Wood BP, Shapiro DL (1988) Surfactant replacement therapy at birth: Final analysis of a clinical trial and comparisons with similar trials. Pediatrics 82:756-762 8. Horbar JD, Soil RF, Sutherland JM, Kotagal U, Philip AGS, Kessler DL, Little GA, Edwards WH, Vidyasagar D, Raju TNK, Jobe AH, Ikegami M, Mullett MD, Myerberg DZ, McAufliffe TL, Lucey JF (1989) A multicenter randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome. N Engl J Med 320:959-965 9. Collaborative European Multicenter Study Group (1988) Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial. Pediatrics 82:683-691 10. Merritt TA, Hallman M (1988) Surfactant replacement. A new era with many challenges for neonatal medicine. Am J Dis Child 142:1333-1339 11. Disse B, Gortner L, Weller E, Eberhardt H, Ziegler H (1988) Efficacy and standardisation of SF-RI 1: a preparation from bovine lung suffactant. In: Lachmann B, ed. Surfactant replacement therapy in neonatal and adult respiratory distress syndrome. Berlin, Heidelberg, New York: Springer-Verlag, pp 37-41 12. Gortner L, Pohlandt F, Disse B, Weller E (in press) Effects of tracheal instillation of bovine surfactant (SF-RI 1) in premature lambs. Eur J Pediatr 13. Gortner L, Pohlandt F, Bartmann P, Disse B (1990) Die Behandlung des Atemnotsyndroms (RDS) sehr kleiner FrCthgeborener mit nattirlichem Surfactant. Monatsschr Kinderheilk 138: 8-12
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14. Toce SS, Farrell PM, Leavitt LA, Samuels DP, Edwards DK (1984) Clinical and roentgenographic scoring systems for assessing bronchopulmonary dysplasia. Am J Dis Child 138:58t585 15. Jobe A, Ikegami M (1987) Surfactant for the treatment of respiratory distress syndrome. Am Rev Respir Dis 136:1256-1275 16. Heicher DA, Kasting DS, Harrod JR (1981) Prospective clinical comparison of two methods for mechanical ventilation of neonates. Rapid rate and short inspiratory time versus slow rate and long inspiratory time. J Pediatr 98:957-961 17. Shankaran S, Slovis TL, Bedard MP, Poland RL (1982) Sonographic classification of intracranial hemorrhage. A prognostic indicator of mortality, morbidity, and short-term neurologic outcome. J Pediatr 100:469-475
