- Email: [email protected]
Pulmonary mechanics and energetics in preterm infants who had respiratory distress syndrome treated with synthetic surfactant
Pulmonary mechanics and energetics in preterm infants who had respiratory distress syndrome treated with synthetic surfactant Vinod K. Bhutani, MD,a Soraya Abbasi, MD,a W a l k e r A. Long, MD,b, c a n d J e f f r e y S. Gerdes, MDa From the Divisionof Neonatology, Universityof Pennsylvania,a Philadelphia, Pennsylvania,the Department of Pediatrics,Universityof North Carolina at Chapel Hill,b and the Clinical Research Division,~ Burroughs Wellcome Co., Research Triangle Park, North Carolina Pulmonary mechanics and energetics were determined in 32 neonates with respiratory distress syndrome, who were randomly assigned to receive treatment with an exogenous synthetic surfactant, Exosurf Neonatal, or air p l a c e b o . Pulmonary mechanics were measured before and 2 hours after surfactant (n = 13) or air p l a c e b o (n = 19) treatment, then l o n g i t u d i n a l l y at 24, 48, and 72 hours after treatment, and again at 7, 14, and 28 days of age. There were no significant differences in the values for pulmonary mechanics or energetics 2 hours after the first dose of surfactant. Improvement in pulmonary mechanics was apparent 24 hours after surfactant treatment, when d y n a m i c c o m p l i a n c e was 36% greater than in the p l a c e b o group (p <0.03). Lung c o m p l i a n c e values were also higher in surfactant-treated infants 48 and 72 hours after treatment, with a m a x i m a l increase of 64% at 7 days of a g e (p <:0.03). Surtactant treatment also caused a significant decrease in total pulmonary resistance at 48 and 72 hours after initial treatment and at 14 days of a g e (p <0.04). Similarly, a decrease in flow-resistive work of breathing was demonstrated 24, 48, and 72 hours after surfactant treatment. At 28 clays of age, pulmonary mechanics were not different in the two groups. We conclude that b e n e f i c i a l effects of surfactant on pulmonary mechanics were not apparent 2 hours after dosing but were evident 24 hours after dosing and persisted for the first 7 to 14 days of life. (J PEDIATR 1992;120:$18-$24)
Decreased pulmonary compliance, reduced tidal volume, and high transpulmonary pressure are the mechanical consequences of neonatal respiratory distress syndrome.l, 2 The alveolar atelectasis of RDS, attributed to surfaetant deficiency, is characterized by decreased functional residual capacity, high pulmonary vascular permeability, and increased lung tissue water. 3, 4 Recent controlled trials have Supported by funds from Burroughs Wellcome Co., Research Triangle Park, N.C. Reprint requests: Vinod Bhutani, MD, Newborn Pediatrics, Pennsylvania Hospital, Eighth and Spruce Streets, Philadelphia, PA 19107. 9/0/35027
S18
demonstrated improvement as a result of treatment with exogenous surfactant. 5-9 A striking feature of these studies has been consistent improvement in respiratory gas exchange within 2 hours of surfactant administration; surprisingly, parallel early effects on pulmonary mechanics have not been apparent in clinical trialsJ ~ PEEP RDS
Positive end-expiratory pressure Respiratory distress syndrome
[
I
In both preterm lambs and baboons, improvement in quasistatic lung compliance was clearly demonstrated immediately after tracheal instillation of exogenous surfacrant j3, 14 However, in preterm infants, when pulmonary
Volume 120 Number 2, Part 2
mechanics were measured sequentially, increased dynamic pulmonary compliance was evident only 24 hours after singlO 5 or multiple 16 doses of exogenous surfactant. Davis et al. 17 have suggested that the effects of surfactant on pulmonary mechanics may be apparent when data are collected during spontaneous breathing but may be masked if measurements are made during mechanical ventilation. We evaluated the immediate effects of exogenous surfactant administered early during RDS. Changes in lung mechanics were determined before and 2 hours after surfactant therapy and during the first 28 days of life; measurements were made during both mechanical ventilation and spontaneous breathing. METHODS
Patient and study protocol. This study was performed at Pennsylvania Hospital, which is participating in multicenter trials of a synthetic surfactant preparation, Exosurf Neonatal (Burroughs Wellcome Co., Research Triangle Park, N.C.). The evaluation s of pulmonary mechanics and energetics were performed concurrently with the clinical trials, but used a separate protocol. All protocols were approved by the Research Review Committee of the Pennsylvania Hospital, and written parental consent was obtained for participation. Infants were enrolled in one of two randomized, placebocontrolled rescue trials of Exosurf Neonatal between July 1988 and October 1989. Preterm infants with a birth weight of more than 1100 gm who met clinical criteria for RDS as defined by the study protocol were randomly selected to receive an initial dose of either surfactant or air placebo between the ages of 2 and 24 hours. All infants received an identical second dose of surfactant or air placebo 12 hours after the first dose. Surfactant or air placebo was administered through the sideport in a special adapter, which connected the ventilator circuit to the endotracheal tube. The dose of Exosurf Neonatal was 5 ml/kg birth weight, which is equivalent to 67.5 mg/kg of dipalmitoylphosphatidylcholine. Detailed descriptions of the rescue surfactant protocols are reported elsewhere. 18' 19 Ventilatory equipment and care, Conventional mechanical ventilation was delivered by a time-cycled, pressurelimited ventilator (Bear Cub, Bournes Medical Co., Riverside, Calif.). Ventilator settings were adjusted to maintain arterial oxygen tension between 60 and 80 mm Hg, arterial carbon dioxide tension between 38 and 50 mm Hg, and the arterial pH between 7.3 and 7.4. In general, the response to improvement in blood gas exchange consisted first of a reduction of peak inflation pressure, followed by a reduction in positive end-expiratory pressure and finally a reduction in inspired oxygen. Endotracheal suctioning was allowed 2 hours after sur-
Lung mechanics after synthetic surfactant
S 19
factant or air placebo therapy, but suctioning was performed only when considered necessary during the first 3 days of life; subsequently, it was performed routinely at 4to 6-hour intervals. Manual bag ventilation was used during suctioning and endotracheal tube replacement. The ventilatory rates and pressures, monitored by a bedside manometer, were the same during manual and conventional ventilation. Bedside evaluation of pulmonary mechanics. Pulmonary mechanics during both spontaneous and mechanical breathing were measured in all study infants. For data collection during spontaneous breathing, the level of PEEP was set at 3 cm H20, and the ventilator rate was decreased to zero for a 45- to 60-second sampling period. In extubated infants, pulmonary function data were measured by a face maskpneumotachometer device. For infants in whom reliable data collection during spontaneous breathing was difficult, such as in those infants with apnea or chest wall distortion, data were collected during mechanical ventilation. The ventilator settings used for data collection were as follows: ventilator system flow, 8 L/min; PEEP, 2 cm H20 rate 60/ rain; and inspiratory time, 0.5 second. The peak inflation pressure needed clinically was maintained. Pulmonary mechanics were measured immediately before and 2, 24, 48, and 72 hours after the initial surfactant or air placebo treatment; subsequently, measurements were repeated at 7, 14, and 28 days of age. Measurement of respiratory signals. The neonates were placed supine with their heads in a neutral position. Sedation was not used. Simultaneous signals of gas flow and transpulmonary pressure were measured and computed for data analysis and graphic display. A thin-walled polyvinyl balloon (Mallinckrodt Corp. , Argyle, N.Y.), 40 mm long, 7.5 mm wide, and containing 0.2 ml of air, was placed in the distal esophagus. A differential pressure transducer (Model P7, Celesco Transducer Products Inc., Canoga Park, Calif.) measured transpulmonary pressure changes as the difference between airway and esophageal pressures. Respiratory gas flow was measured by a pneumotachometer (Fleish Model 00, OEM Medical, Richmond, Va.) with a differential Pressure transducer (Model MP45, Validyne Engineering Co., Northridge, Calif.). These devices were attached to the inlet port of either a face mask or an endotracheal tube and had minimal resistance (13.2 cm H 2 0 / L/see) and dead space (1.7 ml). The tidal volume for each breath was determined by digital integration of the flow signals. The pneumotachometer was calibrated by the use of constant flow rates, and the output was linear from 0 to 0.15 L/see. A water manometer was used to calibrate the pressure transducers. The calibration, sensitivity, and operating techniques of the apparatus are similar to those previously described in detail. 19
S 20
Bhutani et al.
The Journal of Pediatrics February 1992
1.4-
Rescue Placebo Surfactant
1.2-
~ o
1
1.0-
o8_ a-E u o ~E
0,6-
s 0.4-
0.2
0.0Pre Post < 1 Day
1
2
3
7
14
Age (Days) Fig. 4, Dynamic puhnonary compliance from birth to 14 days of age in preterm infants with RDS treated with surfactant or air placebo. Values are mean _+ SEM. All values represent data obtained for either spontaneous or mechanical breathing; number of measurements using spontaneous or mechanical breaths in each group of infants is listed in Table II. Values for pre- (pre) and postintervention (post) at <1 day of age represent paired data only (n = 9) and were assessed by the two-tailed Student t test for paired values. *Significant increase (p <0.03) in surfactant-treated infants compared with placebo-treated infants, as assessed by the two-tailed Student t test for unpaired values. Table I. Patient demographics according to treatment assignment
No, infants enrolled Birth weight (gm) Gestational age (wk) Age at initial dose (hr)
Air placebo
Exosurf Neonatal
19 1853 +_ 602 31.9 _+ 2.1 8+ 1
13 1943 _+ 633 31.8 _+ 2.3 8 +_ 1
Values are means _+SEM. Differences are not significant.
Data analysis for pulmonary functions. Simultaneous records of airflow, volume, and transpulmonary pressure were sampled and recorded at a rate of 75 H z / c h a n n e l by a custom-designed software program. The values for compliance, resistance, and flow-resistive work of breathing were calculated for inspiration, expiration, and total breath. In addition, values for tidal volume, minute ventilation, respiratory frequency, and time constant were obtained. Breaths were accepted for subsequent analysis of mechanics if they met the criteria previously described, z~ Pulmonary mechanics and energetics were calculated by the twofactor least mean squares technique. 2~ Accuracy of data collection. The accurate assessment o f intrapleural pressure changes may be confounded by chest wall distortion. 2~ For this reason, airway occlusion test results 24 and pulmonary graphics, including pressure-volume and flow-volume loops, were monitored. The airway
occlusion test confirmed the adequate placement and function of the esophageal balloon. Pulmonary graphics were evaluated to exclude paradoxic changes in transpulmonary pressure, inversion or reversal of pressure-volume loops, and other unusual configurations suggestive of chest wall distortion, zs Any such breaths were excluded from data analysis. Artifacts in the flow or pressure signals, differences in inspiratory and expiratory tidal volume, or tidal volumes of <3.0 ml were other criteria for rejection of breaths in data analysis. A minimum of 15 breaths (usually 25 to 45) were evaluated, with a correlation coefficient of at least 0.98 required for least mean squares analysis. 2~ The mean value of analyzed breaths was used to represent lung mechanics. Infants were monitored during sampling by a cardiorespiratory monitor and a pulse oximeter. Data sampling was completed within 60 seconds and did not interfere with the infants' care. Inadvertent overdistention of the lungs during mechanical ventilation may alter pulmonary mechanics. 26 Our preliminary observations with manual ventilation frequently indicated pulmonary overdistention. 27 During mechanical ventilation, the possibility that data collected after pulmonary overdistention could be used was minimized by excluding values if the mean tidal volume was at least 8.5 ml/kg. This decision was based on preliminary observations and on the fact that reported normal values for tidal volume in both preterm and term neonates during spontaneous breathing are less than 8.0 ml/kgS, 28, 29
Volume 120 Number 2, Part 2
Lung mechanics after synthetic surfactant
S21
Table II. N u m b e r of infants with satisfactory lung mechanics data and corresponding values for tidal volume
No. infants alive
No. infants with satisfactory mechanic data (spontaneous/mechanical)*
Age
Air placebo
Exosurf Neonatal
Air placebo
Exosurf Neonatal
Pre:~ Post~ 1 Day 2 Days 3 Days 7 Days 14 Days 28 Days
19 19 19 19 19 19 19 19
13 13 13 13 13 13 13 13
1/11 0/12 2/12 2/13 1/14 12/6 14/2 19/0
2/7 2/9 2/9 2/11 4/6 10/3 11/0 13/0
Tidal volumet (ml/kg) Air p l a c e b o 5.1 6.2 5.7 6.3 6.4 5.3 5.8 6.1
• 0.5 _ 0.4 • 0.5 _+ 0.5 • 0.6 • 0.5 • 0.3 • 0.9
Exosurf Neonatal 5.9 5.5 5.4 5.1 5.5 6.6 5.5 6.5
_+ 0.5 5- 0.7 _+ 0.3 ___0.5 __+0.3 _+_0.4 _+ 0.5 ___0.5
*All infants had pulmonary mechanics measured during spontaneous and mechanical breathing. If satisfactory data were available for spontaneous breathing, these were used as first choice. When possible, data collectedduring mechanical breathing were substituted if data collected during spontaneous breathing were not satisfactory. In some infants alI data were excluded because they did not meet standardized criteria. tValues for tidal volumeare mean _+SD; differencesare not statistically significant. :~Pre and post indicate immediatelybefore and 2 hours after surfactant or air placebo administration on day 1.
The team involved in the collection, analysis, and interpretation of pulmonary function data remained blinded to whether patients received surfactant or air placebo therapy. After data analysis was completed, the staff at Burroughs Wellcome Co. provided information on whether each infant received surfactant or air placebo. Statistical analysis. Data were obtained during both spontaneous and mechanical breathing in all patients. If the data for spontaneous breathing were of satisfactory quality, they were accepted preferentially in the primary analysis. If they were not satisfactory, the data for mechanical breaths, if found satisfactory, were substituted. Statistical analysis was performed by multiple linear regression to examine the data as a function of postnatal age. Comparison of values for placeboand surfactant groups at specific postnatal ages was performed with an unpaired, two-tailed Student t test. In a subgroup of nine infants, with measurements both before and 2 hours after the initial surfactant or placebo treatment, data were compared with a two-tailed Student t test for paired values. RESULTS Thirty-two infants were enrolled; all survived at least 28 days and completed the lung mechanics protocol. The air placebo- and surfactant-treated groups were well matched in gestational age, birth weight, and age at first treatment with surfactant or air placebo (Table I). The number of infants who met our criteria for the accurate measurement of pulmonary mechanics during spontaneous or mechanical breathing is listed in Table II. The number of infants in whom satisfactory measurements could be made during spontaneous breathing was initially low; therefore data for mechanical breathing were substi-
tuted, but the number of infants with satisfactory measurements during spontaneous breathing improved as the infants grew. Values for tidal volume during the study period are also listed in Table II; no statistically significant differences in tidal volume were observed in infants after surfactant therapy.
Comparison of data for spontaneous and mechanical breathing. In 15 infants who bad satisfactory data for both spontaneous and mechanical breathing, there were no significant differences for any measurement of pulmonary mechanics and energetics, as defined by our standardized criteria (data not shown). Effect of postnatal age on pulmonary mechanics in RDS. As seen in Fig. 1, during the first week of life, dynamic lung compliance increased significantly as a function of postnatal age in both air placebo-treated (p <0.001) and surfactant-treated infants (p <0.005). With placebo, dynamic lung compliance increased from 0.28 m l / c m H 2 0 at 1 day of age to 0.65 m l / c m H 2 0 at 7 days of age. With surfacrant, dynamic lung compliance increased from 0.38 m l / c m H 2 0 at 1 day of age to 1.04 m l / c m H 2 0 at 7 days of age. In contrast, the reductions in pulmonary resistance over the first 14 days of life were not statistically significant in either group (Fig. 2). Effects of surfactant therapy 2 hours after dosing. The effects of synthetic surfactant on pulmonary mechanics and energetics in nine infants, who had measurements both before and 2 hours after initial treatment, are shown in Figs. 1 and 2 and in Table III; no significant differences were demonstrated 2 hours after dosing in any of the variables for lung mechanics and energetics. Similarly no differences were detected at 2 hours with a secondary analysis of mechanical breathing alone; data for spontaneous breath-
S 22
Bhutani et al.
The Journal ofPediatrics February1992
200- Rescue
150-
o9
~ - j Placebo Surfactant
o o 5 .~m ~O
100-
~Eo 2_ 50
Pre Post <1 Day
i
3
7
14
Age (Days) t:i9. 2. Total pulmonary resistance from birth to 14 days of age in preterm infants with RDS treated with surfactant or air placebo. Values are mean _+ SEM. All values represent data obtained for either spontaneousor mechanical breathing; number of measurements using spontaneous or mechanical breaths in each group of infants is listed in Table II. Values for pre- (,ore) and postintervention (post) at < 1 day of age represent paired data only (n = 9) and were assessed by the twotailed Student t test for paired values. *Significant decrease (p < 0.05) in surfactant-treated infants, as assessed by the two-tailed Student t test for unpaired values.
ing alone at 2 hours were not sufficient for statistical evaluation. Subsequent effects of surfactant therapy. Surfactant treatment was associated with significantly higher values for dynamic pulmonary compliance compared with air placebo treatment at 24, 48, and 72 hours after the initial intervention and at 7 days of age (Fig. 1). The improvement was 36% at 24 hours and 37% at 72 hours after the initial intervention and 60% at 7 days of age. These data are for spontaneous breathing, with data from mechanical breathing substituted when necessary, as indicated in Table II. In a secondary analysis, similar results were obtained when data for spontaneous breathing alone were evaluated (data not shown). With surfactant treatment, infants with RDS had significantly lower values for total pulmonary resistance at 48 hours and 72 hours after intervention and at 14 days of age compared with placebo-treated infants (Fig. 2). The improvement was 31% at both 48 and 72 hours after intervention and 33% at 14 days of age. There was significantly lower flow-resistive work of breathing in the surfactant-treated group compared with the placebo-treated group at 24, 48, and 72 hours after the initial intervention (Table IIl). Pulmonary mechanics and energetics at 28 days of age. The surfactant- and placebo-treated groups had similar values for lung mechanics and energetics at the age of 28 days (Table IV).
DISCUSSION In this prospective, randomized, placebo-controlled study, we found that endotracheal administration of Exosurf Neonatal in ventilated infants with RDS improved pulmonary mechanics and energetics during the first week of life. Pulmonary dysfunction in the placebo group was considerable compared with infants of normal term gestation ~, 2, 28 and non-ventilated, low birth weight infants.29 The longitudinal changes in pulmonary mechanics in the placebo group reflect the natural resolution of RDS treated with conventional ventilation alone. Infants whose birth weight was greater than l 100 gm who received two doses of surfactant within 24 hours of birth had significant improvements in pulmonary mechanics and energetics. Although this effect was not evident within 2 hours of surfactant therapy, it was demonstrable at 24, 48, and 72 hours after the initial intervention, and at 7 to 14 days of age. In infants treated with surfactant, pulmonary compliance values were comparable with those of nonventilated, low birth weight infants of similar gestational and postnatal age. 29 At 28 days of age, pulmonary compliance in both the surfactant and placebo groups approached that of nonventilated, low birth weight infants. Pulmonary compliance of nonventilated infants of 30 to 32 weeks gestation at 28 days postnatal age has been reported as 1.25 ml/cm H20/kg. 29 Our results are in agreement with those of Bhat et al. 15 and Couser et al. Is Treatment with two rescue doses of sur-
Volume 120 Number 2, Part 2
Lung mechanics after synthetic surfactant
Table Ill. Effect of surfactant treatment on flow resistive work of breathing (gm. c m / k g )
Age
Air placebo
Exosurf Neonatal
Pre Post 1 Day 2 Days 3 Days 7 Days 14 Days 28 Days
32 +_ 6 44 + 5 36_+ 6 49 _+ 7 43 + 5 36 + 5 24 + 3 23 _+ 5
40 _+ 8 29_+ 6 27 + 5* 25 _+ 4* 27 _+ 7* 26 _+ 12 25 _+ 2 26 + 7
Values are mean _+SEM. *Significant difference between surfactant- and placebo-treated infants (p <0.5), as assessed by two-tailedStudent t test for unpaired values.All data were obtained from spontaneous or mechanical breathing; number of measurements using spontaneous or mechanicalbreaths in each group of infants is indicated in Table II.
factant in our study resulted in 36% and 60% improvements in dynamic pulmonary compliance at 1 and 7 days of age, respectively, compared with 50% and 94% improvements at ages 1 and 7 days, respectively, after three or four doses of a different exogenous surfactant. 16 These other investigators15, 16 have found that for data collected during mechanical ventilation, improvements in lung compliance were only apparent 24 hours after intervention with exogenous surfactant. Our observations were similar; we were also unable to demonstrate improved pulmonary mechanics 2 hours after surfactant therapy. Although Davis et al. 17 have suggested that collecting data during spontaneous breathing might facilitate detection of improved pulmonary mechanics, in our study, accurate measurements in spontaneously breathing infants at an early age were not obtained frequently enough for statistical analysis. Mechanical ventilator breathing is known to inadvertently overdistend the lung as a consequence of inappropriate inspiratory time, excessive inflation pressure, and inadvertent PEEP; unusually high tidal volumes and distorted pressure-volume loops can result. 26' 27 These problems may be eliminated by rigidly standardizing the mechanical breath data collection, as described in the Methods section. Excluding mechanical breaths with pulmonary overdistention facilitates data analysis and interpretation. 2~176 When possible, we used the data from spontaneous breathing alone. Because we wished to optimize the number of infants in the study, we elected to include data from mechanical ventilation, provided it was obtained without lung overdistention; the overall results were similar to those for spontaneous breathing alone. Based on the known pathophysiology of RDS, we expected to see a striking early improvement in pulmonary compliance after surfactant treatment in infants with RDS.
S 23
Table IV. Pulmonary mechanics and energetics at 28 days of age after surfactant or placebo treatment on first day of life
Weight at time of study (gin) Tidal volume (ml/kg) Frequency (breaths/ rain) Flow-resistive work (gm- cm/kg) Pulmonary compliance (ml/cm H20/kg) Pulmonary resistance (cm H20/L/sec)
Air placebo (n = 19)
Exosurf Neonatal (n = 13)
1996 _+ 148
1950 _+ 124
6.1 _+ 0.9
6.5 _+ 0.5
65 _+ 3.8
60 _+ 4.3
23.1 _+ 5.5
26.1 _+ 6.8
1.03 _ 0.14
1.21 + 0.12
61.9 +_ 12.6
66.2 _+ 8.6
Values are mean + SEM. Differences are not significant.
Recent studies 15, ~6 and our data indicate that improvement occurs later than anticipated. The effects of surfactant on functional residual capacity in infants with R D S are insufficiently studied; however, accurate determination of lung volume in sick preterm infants is difficult with current technology. From a physiologic perspective, the mechanisms of improvement in pulmonary gas exchange before demonstrable changes in pulmonary mechanics remain to be elucidated. In summary, evaluation of puhnonary mechanics and energetics in infants in the acute phase of R D S demonstrated substantial improvement during the first week of life. This improvement was more rapid if synthetic surfactant was given. We acknowledge Emido Sivieri, Karen Karp, Mary Grous, Mary McGowan, William Sieberlich, Susan Myers, Patricia Lawlor, and the staff at Burroughs Wellcome Co. REFERENCES
1. Bancalari E. Pulmonary function testing and other diagnostic laboratory procedures. In: Thibeault DW, Gary GA, eds. Neonatal pulmonary care. Norwalk, Conn.: Appleton Century Crofts, 1986:195-234. 2. Clutario BC. Clinical pulmonary function. In: Scarpelli EM, ed. Pulmonary physiology of the fetus, newborn and child. Philadelphia: Lea and Febiger, 1975:299-325. 3. Jobe A, Ikegami M, Jacobs H, et al. Permeability of premature lamb lungs to protein and the effect of surfactant on that permeability. J Appl Physiol 1983;55:169-76. 4. Robertson R, Berry D, Curstedt T, et al. Leakage of protein in the immature rabbit lung. Effect of surfactant replacement. Respir Physiol 1985;61:265-76.
S24
Bhutani et al.
5. Kwong MS, Egan EA. Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 1985;76: 585-92. 6. Merritt TA, Hallman M, Bloom BT, et al. Prophylactic treatment of very premature infants with human surfactant. N Engl J Med 1986;315:785-90. 7. Raju TNK, Vidyasagar D, Bhat R, et al. Double-blind controlled trial of single dose treatment with bovine surfactant in severe hyaline membrane disease. Lancet 1987;1:651-6. 8. Horbar JD, Soll RF, Sutherland JM, et al. A multicenter randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome. N Engl J Med 1989;320:959-65. 9. Lang M J, Hall RT, Reddy NS, et al. A controlled trial of human surfactant replacement therapy for severe respiratory distress syndrome in very low birth weight infants. J P~DIATR 1990;116:295-300. 10. Milner A, Vyas H, Hopkins I, et al. Effects of artificial surfactant on lung function and blood gases in idiopathic respiratory distress syndrome. Arch Dis Child 1983;58:458-61. 11. Milner A, Vyas H, Hopkins I, et al. Effects of exogenous surfactant on total respiratory system compliance. Arch Dis Child 1984;59:369-71. 12. Mannino F, Merritt AT, Hallman M, et al. Surfactant treatment in neonates with severe RDS improves oxygenation without improving dynamic lung compliance [Abstract]. Pediatr Res 1985;19:409A. 13. Jobe A, Ikegami M, Glatz T, et al. Duration and characteristics of treatment of premature lambs with natural surfactant. J Clin Invest 1981;67:370-5. 14. Vidyasagar D, Maeta H, Raju TNK, et al. Bovine surfactant (surfactant TA) therapy in immature baboons with hyaline membrane disease. Pediatrics 1985;75:1132-6. 15. Bhat R, Dziedzic K, Bhutani VK, Vidyasager D. Effect of single dose surfactant on pulmonary function. Crit Care Med 1990;18:590-5. 16. Couser R J, Ferrara TB, Ebert J, et al. Effects of exogenous surfactant therapy on dynamic compliance during mechanical breathing in preterm infants with hyaline membrane disease. J PED~ATR 1990;116:119-24. 17. Davis JM, Veness-Meehan K, Notter RH, et al. Changes in pulmonary mechanics after the administration of surfactant to infants with respiratory distress syndrome. N Engl J Med 1988;319:476-9. 18. Long W, Thompson T, Sundell H, et al. Effects of two rescue
The Journal of Pediatrics February 1992
19.
20.
21. 22.
23. 24.
25.
26.
27.
28.
29.
30.
doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome. J PEt~IATR 1991; 118:595-605. Long W, Corbet A, Cotton R, et al., the American Exosurf Neonatal Study Group I, and the Canadian Exosurf Neonatal Study Group. A controlled trial of synthetic surfactant in infants weighing 1250 g or more with respiratory distress syndrome. N Engl J Med 1991;325:1696-703. Bhutani VK, Sivieri EM, Abbasi S, Shaffer TM. Evaluation of neonatal pulmonary mechanics: two factor least mean-square analysis technique. Pediatr Pulmonol 1988;4:150-8. Gerhardt T, Bancalari E. Chest wall compliance in fnll-term and premature infants. Acta Pediatr Scand 1980;59:359-64. LeSnuef PN, Lopes JM, England S J, et al. Influence of chest wall distortion on esophageal pressure. J Appl Physiol 1983;55: 353-8. Heldt GP, Mcllroy MB. Distortion of chest wall and work of diaphragm in preterm infants. J Appl Physiol 1987;62:164-9. Sly PD, Brown KA, Bates JHT, et al. Noninvasive determination of respiratory mechanics during mechanical ventilation of neonates: a review of current and future techniques. Pediatr Pulmonol 1988;4:39-47. Bhutani VK. Pulmonary function profile: computer analysis and pulmonary graphics. In: Bhutani VK, Shaffer TH, Vidyasager D, eds. Neonatal pulmonary function testing: physiological, technical and clinical considerations. Ithaca, N.Y.: Perinatology Press, 1988;13-33. Mammel MC, Fisher JB, Bing DR, et al. Effect of spontaneous and mechanical breathing on dynamic lung mechanics in hyaline membrane disease. Pediatr Pulmonol 1990;8:222-5. Sivieri E, Abbasi S, Bhutani VK. On-line pulmonary graphics for assistance in the manual ventilation of neonates. In: Gennser G, Marsal K, Svenninsen N, Lindstrom K, eds. Fetal and neonatal physiological measurements, vol III. Malmo, Sweden: Department of Obstetrics and Gynecology, Malmo General Hospital, 1989;425-9. Gerhardt T, Hehre D, Feller R, et al. Pulmonary mechanics in normal infants and young children during first 5 years of life. Pediatr Pulmonol 1987;3:309-16. Abbasi S, Bhutani VK. Pulmonary mechanics and energetics of normal, non-ventilated low birth weight infants. Pediatr Pulmonol 1990;8:89-95. McCann EM, Goldman SL, Brady JP. Pulmonary function in the sick newborn infant. Pediatr Res 1987;21:313-25.
Decreased pulmonary compliance, reduced tidal volume, and high transpulmonary pressure are the mechanical consequences of neonatal respiratory distress syndrome.l, 2 The alveolar atelectasis of RDS, attributed to surfaetant deficiency, is characterized by decreased functional residual capacity, high pulmonary vascular permeability, and increased lung tissue water. 3, 4 Recent controlled trials have Supported by funds from Burroughs Wellcome Co., Research Triangle Park, N.C. Reprint requests: Vinod Bhutani, MD, Newborn Pediatrics, Pennsylvania Hospital, Eighth and Spruce Streets, Philadelphia, PA 19107. 9/0/35027
S18
demonstrated improvement as a result of treatment with exogenous surfactant. 5-9 A striking feature of these studies has been consistent improvement in respiratory gas exchange within 2 hours of surfactant administration; surprisingly, parallel early effects on pulmonary mechanics have not been apparent in clinical trialsJ ~ PEEP RDS
Positive end-expiratory pressure Respiratory distress syndrome
[
I
In both preterm lambs and baboons, improvement in quasistatic lung compliance was clearly demonstrated immediately after tracheal instillation of exogenous surfacrant j3, 14 However, in preterm infants, when pulmonary
Volume 120 Number 2, Part 2
mechanics were measured sequentially, increased dynamic pulmonary compliance was evident only 24 hours after singlO 5 or multiple 16 doses of exogenous surfactant. Davis et al. 17 have suggested that the effects of surfactant on pulmonary mechanics may be apparent when data are collected during spontaneous breathing but may be masked if measurements are made during mechanical ventilation. We evaluated the immediate effects of exogenous surfactant administered early during RDS. Changes in lung mechanics were determined before and 2 hours after surfactant therapy and during the first 28 days of life; measurements were made during both mechanical ventilation and spontaneous breathing. METHODS
Patient and study protocol. This study was performed at Pennsylvania Hospital, which is participating in multicenter trials of a synthetic surfactant preparation, Exosurf Neonatal (Burroughs Wellcome Co., Research Triangle Park, N.C.). The evaluation s of pulmonary mechanics and energetics were performed concurrently with the clinical trials, but used a separate protocol. All protocols were approved by the Research Review Committee of the Pennsylvania Hospital, and written parental consent was obtained for participation. Infants were enrolled in one of two randomized, placebocontrolled rescue trials of Exosurf Neonatal between July 1988 and October 1989. Preterm infants with a birth weight of more than 1100 gm who met clinical criteria for RDS as defined by the study protocol were randomly selected to receive an initial dose of either surfactant or air placebo between the ages of 2 and 24 hours. All infants received an identical second dose of surfactant or air placebo 12 hours after the first dose. Surfactant or air placebo was administered through the sideport in a special adapter, which connected the ventilator circuit to the endotracheal tube. The dose of Exosurf Neonatal was 5 ml/kg birth weight, which is equivalent to 67.5 mg/kg of dipalmitoylphosphatidylcholine. Detailed descriptions of the rescue surfactant protocols are reported elsewhere. 18' 19 Ventilatory equipment and care, Conventional mechanical ventilation was delivered by a time-cycled, pressurelimited ventilator (Bear Cub, Bournes Medical Co., Riverside, Calif.). Ventilator settings were adjusted to maintain arterial oxygen tension between 60 and 80 mm Hg, arterial carbon dioxide tension between 38 and 50 mm Hg, and the arterial pH between 7.3 and 7.4. In general, the response to improvement in blood gas exchange consisted first of a reduction of peak inflation pressure, followed by a reduction in positive end-expiratory pressure and finally a reduction in inspired oxygen. Endotracheal suctioning was allowed 2 hours after sur-
Lung mechanics after synthetic surfactant
S 19
factant or air placebo therapy, but suctioning was performed only when considered necessary during the first 3 days of life; subsequently, it was performed routinely at 4to 6-hour intervals. Manual bag ventilation was used during suctioning and endotracheal tube replacement. The ventilatory rates and pressures, monitored by a bedside manometer, were the same during manual and conventional ventilation. Bedside evaluation of pulmonary mechanics. Pulmonary mechanics during both spontaneous and mechanical breathing were measured in all study infants. For data collection during spontaneous breathing, the level of PEEP was set at 3 cm H20, and the ventilator rate was decreased to zero for a 45- to 60-second sampling period. In extubated infants, pulmonary function data were measured by a face maskpneumotachometer device. For infants in whom reliable data collection during spontaneous breathing was difficult, such as in those infants with apnea or chest wall distortion, data were collected during mechanical ventilation. The ventilator settings used for data collection were as follows: ventilator system flow, 8 L/min; PEEP, 2 cm H20 rate 60/ rain; and inspiratory time, 0.5 second. The peak inflation pressure needed clinically was maintained. Pulmonary mechanics were measured immediately before and 2, 24, 48, and 72 hours after the initial surfactant or air placebo treatment; subsequently, measurements were repeated at 7, 14, and 28 days of age. Measurement of respiratory signals. The neonates were placed supine with their heads in a neutral position. Sedation was not used. Simultaneous signals of gas flow and transpulmonary pressure were measured and computed for data analysis and graphic display. A thin-walled polyvinyl balloon (Mallinckrodt Corp. , Argyle, N.Y.), 40 mm long, 7.5 mm wide, and containing 0.2 ml of air, was placed in the distal esophagus. A differential pressure transducer (Model P7, Celesco Transducer Products Inc., Canoga Park, Calif.) measured transpulmonary pressure changes as the difference between airway and esophageal pressures. Respiratory gas flow was measured by a pneumotachometer (Fleish Model 00, OEM Medical, Richmond, Va.) with a differential Pressure transducer (Model MP45, Validyne Engineering Co., Northridge, Calif.). These devices were attached to the inlet port of either a face mask or an endotracheal tube and had minimal resistance (13.2 cm H 2 0 / L/see) and dead space (1.7 ml). The tidal volume for each breath was determined by digital integration of the flow signals. The pneumotachometer was calibrated by the use of constant flow rates, and the output was linear from 0 to 0.15 L/see. A water manometer was used to calibrate the pressure transducers. The calibration, sensitivity, and operating techniques of the apparatus are similar to those previously described in detail. 19
S 20
Bhutani et al.
The Journal of Pediatrics February 1992
1.4-
Rescue Placebo Surfactant
1.2-
~ o
1
1.0-
o8_ a-E u o ~E
0,6-
s 0.4-
0.2
0.0Pre Post < 1 Day
1
2
3
7
14
Age (Days) Fig. 4, Dynamic puhnonary compliance from birth to 14 days of age in preterm infants with RDS treated with surfactant or air placebo. Values are mean _+ SEM. All values represent data obtained for either spontaneous or mechanical breathing; number of measurements using spontaneous or mechanical breaths in each group of infants is listed in Table II. Values for pre- (pre) and postintervention (post) at <1 day of age represent paired data only (n = 9) and were assessed by the two-tailed Student t test for paired values. *Significant increase (p <0.03) in surfactant-treated infants compared with placebo-treated infants, as assessed by the two-tailed Student t test for unpaired values. Table I. Patient demographics according to treatment assignment
No, infants enrolled Birth weight (gm) Gestational age (wk) Age at initial dose (hr)
Air placebo
Exosurf Neonatal
19 1853 +_ 602 31.9 _+ 2.1 8+ 1
13 1943 _+ 633 31.8 _+ 2.3 8 +_ 1
Values are means _+SEM. Differences are not significant.
Data analysis for pulmonary functions. Simultaneous records of airflow, volume, and transpulmonary pressure were sampled and recorded at a rate of 75 H z / c h a n n e l by a custom-designed software program. The values for compliance, resistance, and flow-resistive work of breathing were calculated for inspiration, expiration, and total breath. In addition, values for tidal volume, minute ventilation, respiratory frequency, and time constant were obtained. Breaths were accepted for subsequent analysis of mechanics if they met the criteria previously described, z~ Pulmonary mechanics and energetics were calculated by the twofactor least mean squares technique. 2~ Accuracy of data collection. The accurate assessment o f intrapleural pressure changes may be confounded by chest wall distortion. 2~ For this reason, airway occlusion test results 24 and pulmonary graphics, including pressure-volume and flow-volume loops, were monitored. The airway
occlusion test confirmed the adequate placement and function of the esophageal balloon. Pulmonary graphics were evaluated to exclude paradoxic changes in transpulmonary pressure, inversion or reversal of pressure-volume loops, and other unusual configurations suggestive of chest wall distortion, zs Any such breaths were excluded from data analysis. Artifacts in the flow or pressure signals, differences in inspiratory and expiratory tidal volume, or tidal volumes of <3.0 ml were other criteria for rejection of breaths in data analysis. A minimum of 15 breaths (usually 25 to 45) were evaluated, with a correlation coefficient of at least 0.98 required for least mean squares analysis. 2~ The mean value of analyzed breaths was used to represent lung mechanics. Infants were monitored during sampling by a cardiorespiratory monitor and a pulse oximeter. Data sampling was completed within 60 seconds and did not interfere with the infants' care. Inadvertent overdistention of the lungs during mechanical ventilation may alter pulmonary mechanics. 26 Our preliminary observations with manual ventilation frequently indicated pulmonary overdistention. 27 During mechanical ventilation, the possibility that data collected after pulmonary overdistention could be used was minimized by excluding values if the mean tidal volume was at least 8.5 ml/kg. This decision was based on preliminary observations and on the fact that reported normal values for tidal volume in both preterm and term neonates during spontaneous breathing are less than 8.0 ml/kgS, 28, 29
Volume 120 Number 2, Part 2
Lung mechanics after synthetic surfactant
S21
Table II. N u m b e r of infants with satisfactory lung mechanics data and corresponding values for tidal volume
No. infants alive
No. infants with satisfactory mechanic data (spontaneous/mechanical)*
Age
Air placebo
Exosurf Neonatal
Air placebo
Exosurf Neonatal
Pre:~ Post~ 1 Day 2 Days 3 Days 7 Days 14 Days 28 Days
19 19 19 19 19 19 19 19
13 13 13 13 13 13 13 13
1/11 0/12 2/12 2/13 1/14 12/6 14/2 19/0
2/7 2/9 2/9 2/11 4/6 10/3 11/0 13/0
Tidal volumet (ml/kg) Air p l a c e b o 5.1 6.2 5.7 6.3 6.4 5.3 5.8 6.1
• 0.5 _ 0.4 • 0.5 _+ 0.5 • 0.6 • 0.5 • 0.3 • 0.9
Exosurf Neonatal 5.9 5.5 5.4 5.1 5.5 6.6 5.5 6.5
_+ 0.5 5- 0.7 _+ 0.3 ___0.5 __+0.3 _+_0.4 _+ 0.5 ___0.5
*All infants had pulmonary mechanics measured during spontaneous and mechanical breathing. If satisfactory data were available for spontaneous breathing, these were used as first choice. When possible, data collectedduring mechanical breathing were substituted if data collected during spontaneous breathing were not satisfactory. In some infants alI data were excluded because they did not meet standardized criteria. tValues for tidal volumeare mean _+SD; differencesare not statistically significant. :~Pre and post indicate immediatelybefore and 2 hours after surfactant or air placebo administration on day 1.
The team involved in the collection, analysis, and interpretation of pulmonary function data remained blinded to whether patients received surfactant or air placebo therapy. After data analysis was completed, the staff at Burroughs Wellcome Co. provided information on whether each infant received surfactant or air placebo. Statistical analysis. Data were obtained during both spontaneous and mechanical breathing in all patients. If the data for spontaneous breathing were of satisfactory quality, they were accepted preferentially in the primary analysis. If they were not satisfactory, the data for mechanical breaths, if found satisfactory, were substituted. Statistical analysis was performed by multiple linear regression to examine the data as a function of postnatal age. Comparison of values for placeboand surfactant groups at specific postnatal ages was performed with an unpaired, two-tailed Student t test. In a subgroup of nine infants, with measurements both before and 2 hours after the initial surfactant or placebo treatment, data were compared with a two-tailed Student t test for paired values. RESULTS Thirty-two infants were enrolled; all survived at least 28 days and completed the lung mechanics protocol. The air placebo- and surfactant-treated groups were well matched in gestational age, birth weight, and age at first treatment with surfactant or air placebo (Table I). The number of infants who met our criteria for the accurate measurement of pulmonary mechanics during spontaneous or mechanical breathing is listed in Table II. The number of infants in whom satisfactory measurements could be made during spontaneous breathing was initially low; therefore data for mechanical breathing were substi-
tuted, but the number of infants with satisfactory measurements during spontaneous breathing improved as the infants grew. Values for tidal volume during the study period are also listed in Table II; no statistically significant differences in tidal volume were observed in infants after surfactant therapy.
Comparison of data for spontaneous and mechanical breathing. In 15 infants who bad satisfactory data for both spontaneous and mechanical breathing, there were no significant differences for any measurement of pulmonary mechanics and energetics, as defined by our standardized criteria (data not shown). Effect of postnatal age on pulmonary mechanics in RDS. As seen in Fig. 1, during the first week of life, dynamic lung compliance increased significantly as a function of postnatal age in both air placebo-treated (p <0.001) and surfactant-treated infants (p <0.005). With placebo, dynamic lung compliance increased from 0.28 m l / c m H 2 0 at 1 day of age to 0.65 m l / c m H 2 0 at 7 days of age. With surfacrant, dynamic lung compliance increased from 0.38 m l / c m H 2 0 at 1 day of age to 1.04 m l / c m H 2 0 at 7 days of age. In contrast, the reductions in pulmonary resistance over the first 14 days of life were not statistically significant in either group (Fig. 2). Effects of surfactant therapy 2 hours after dosing. The effects of synthetic surfactant on pulmonary mechanics and energetics in nine infants, who had measurements both before and 2 hours after initial treatment, are shown in Figs. 1 and 2 and in Table III; no significant differences were demonstrated 2 hours after dosing in any of the variables for lung mechanics and energetics. Similarly no differences were detected at 2 hours with a secondary analysis of mechanical breathing alone; data for spontaneous breath-
S 22
Bhutani et al.
The Journal ofPediatrics February1992
200- Rescue
150-
o9
~ - j Placebo Surfactant
o o 5 .~m ~O
100-
~Eo 2_ 50
Pre Post <1 Day
i
3
7
14
Age (Days) t:i9. 2. Total pulmonary resistance from birth to 14 days of age in preterm infants with RDS treated with surfactant or air placebo. Values are mean _+ SEM. All values represent data obtained for either spontaneousor mechanical breathing; number of measurements using spontaneous or mechanical breaths in each group of infants is listed in Table II. Values for pre- (,ore) and postintervention (post) at < 1 day of age represent paired data only (n = 9) and were assessed by the twotailed Student t test for paired values. *Significant decrease (p < 0.05) in surfactant-treated infants, as assessed by the two-tailed Student t test for unpaired values.
ing alone at 2 hours were not sufficient for statistical evaluation. Subsequent effects of surfactant therapy. Surfactant treatment was associated with significantly higher values for dynamic pulmonary compliance compared with air placebo treatment at 24, 48, and 72 hours after the initial intervention and at 7 days of age (Fig. 1). The improvement was 36% at 24 hours and 37% at 72 hours after the initial intervention and 60% at 7 days of age. These data are for spontaneous breathing, with data from mechanical breathing substituted when necessary, as indicated in Table II. In a secondary analysis, similar results were obtained when data for spontaneous breathing alone were evaluated (data not shown). With surfactant treatment, infants with RDS had significantly lower values for total pulmonary resistance at 48 hours and 72 hours after intervention and at 14 days of age compared with placebo-treated infants (Fig. 2). The improvement was 31% at both 48 and 72 hours after intervention and 33% at 14 days of age. There was significantly lower flow-resistive work of breathing in the surfactant-treated group compared with the placebo-treated group at 24, 48, and 72 hours after the initial intervention (Table IIl). Pulmonary mechanics and energetics at 28 days of age. The surfactant- and placebo-treated groups had similar values for lung mechanics and energetics at the age of 28 days (Table IV).
DISCUSSION In this prospective, randomized, placebo-controlled study, we found that endotracheal administration of Exosurf Neonatal in ventilated infants with RDS improved pulmonary mechanics and energetics during the first week of life. Pulmonary dysfunction in the placebo group was considerable compared with infants of normal term gestation ~, 2, 28 and non-ventilated, low birth weight infants.29 The longitudinal changes in pulmonary mechanics in the placebo group reflect the natural resolution of RDS treated with conventional ventilation alone. Infants whose birth weight was greater than l 100 gm who received two doses of surfactant within 24 hours of birth had significant improvements in pulmonary mechanics and energetics. Although this effect was not evident within 2 hours of surfactant therapy, it was demonstrable at 24, 48, and 72 hours after the initial intervention, and at 7 to 14 days of age. In infants treated with surfactant, pulmonary compliance values were comparable with those of nonventilated, low birth weight infants of similar gestational and postnatal age. 29 At 28 days of age, pulmonary compliance in both the surfactant and placebo groups approached that of nonventilated, low birth weight infants. Pulmonary compliance of nonventilated infants of 30 to 32 weeks gestation at 28 days postnatal age has been reported as 1.25 ml/cm H20/kg. 29 Our results are in agreement with those of Bhat et al. 15 and Couser et al. Is Treatment with two rescue doses of sur-
Volume 120 Number 2, Part 2
Lung mechanics after synthetic surfactant
Table Ill. Effect of surfactant treatment on flow resistive work of breathing (gm. c m / k g )
Age
Air placebo
Exosurf Neonatal
Pre Post 1 Day 2 Days 3 Days 7 Days 14 Days 28 Days
32 +_ 6 44 + 5 36_+ 6 49 _+ 7 43 + 5 36 + 5 24 + 3 23 _+ 5
40 _+ 8 29_+ 6 27 + 5* 25 _+ 4* 27 _+ 7* 26 _+ 12 25 _+ 2 26 + 7
Values are mean _+SEM. *Significant difference between surfactant- and placebo-treated infants (p <0.5), as assessed by two-tailedStudent t test for unpaired values.All data were obtained from spontaneous or mechanical breathing; number of measurements using spontaneous or mechanicalbreaths in each group of infants is indicated in Table II.
factant in our study resulted in 36% and 60% improvements in dynamic pulmonary compliance at 1 and 7 days of age, respectively, compared with 50% and 94% improvements at ages 1 and 7 days, respectively, after three or four doses of a different exogenous surfactant. 16 These other investigators15, 16 have found that for data collected during mechanical ventilation, improvements in lung compliance were only apparent 24 hours after intervention with exogenous surfactant. Our observations were similar; we were also unable to demonstrate improved pulmonary mechanics 2 hours after surfactant therapy. Although Davis et al. 17 have suggested that collecting data during spontaneous breathing might facilitate detection of improved pulmonary mechanics, in our study, accurate measurements in spontaneously breathing infants at an early age were not obtained frequently enough for statistical analysis. Mechanical ventilator breathing is known to inadvertently overdistend the lung as a consequence of inappropriate inspiratory time, excessive inflation pressure, and inadvertent PEEP; unusually high tidal volumes and distorted pressure-volume loops can result. 26' 27 These problems may be eliminated by rigidly standardizing the mechanical breath data collection, as described in the Methods section. Excluding mechanical breaths with pulmonary overdistention facilitates data analysis and interpretation. 2~176 When possible, we used the data from spontaneous breathing alone. Because we wished to optimize the number of infants in the study, we elected to include data from mechanical ventilation, provided it was obtained without lung overdistention; the overall results were similar to those for spontaneous breathing alone. Based on the known pathophysiology of RDS, we expected to see a striking early improvement in pulmonary compliance after surfactant treatment in infants with RDS.
S 23
Table IV. Pulmonary mechanics and energetics at 28 days of age after surfactant or placebo treatment on first day of life
Weight at time of study (gin) Tidal volume (ml/kg) Frequency (breaths/ rain) Flow-resistive work (gm- cm/kg) Pulmonary compliance (ml/cm H20/kg) Pulmonary resistance (cm H20/L/sec)
Air placebo (n = 19)
Exosurf Neonatal (n = 13)
1996 _+ 148
1950 _+ 124
6.1 _+ 0.9
6.5 _+ 0.5
65 _+ 3.8
60 _+ 4.3
23.1 _+ 5.5
26.1 _+ 6.8
1.03 _ 0.14
1.21 + 0.12
61.9 +_ 12.6
66.2 _+ 8.6
Values are mean + SEM. Differences are not significant.
Recent studies 15, ~6 and our data indicate that improvement occurs later than anticipated. The effects of surfactant on functional residual capacity in infants with R D S are insufficiently studied; however, accurate determination of lung volume in sick preterm infants is difficult with current technology. From a physiologic perspective, the mechanisms of improvement in pulmonary gas exchange before demonstrable changes in pulmonary mechanics remain to be elucidated. In summary, evaluation of puhnonary mechanics and energetics in infants in the acute phase of R D S demonstrated substantial improvement during the first week of life. This improvement was more rapid if synthetic surfactant was given. We acknowledge Emido Sivieri, Karen Karp, Mary Grous, Mary McGowan, William Sieberlich, Susan Myers, Patricia Lawlor, and the staff at Burroughs Wellcome Co. REFERENCES
1. Bancalari E. Pulmonary function testing and other diagnostic laboratory procedures. In: Thibeault DW, Gary GA, eds. Neonatal pulmonary care. Norwalk, Conn.: Appleton Century Crofts, 1986:195-234. 2. Clutario BC. Clinical pulmonary function. In: Scarpelli EM, ed. Pulmonary physiology of the fetus, newborn and child. Philadelphia: Lea and Febiger, 1975:299-325. 3. Jobe A, Ikegami M, Jacobs H, et al. Permeability of premature lamb lungs to protein and the effect of surfactant on that permeability. J Appl Physiol 1983;55:169-76. 4. Robertson R, Berry D, Curstedt T, et al. Leakage of protein in the immature rabbit lung. Effect of surfactant replacement. Respir Physiol 1985;61:265-76.
S24
Bhutani et al.
5. Kwong MS, Egan EA. Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 1985;76: 585-92. 6. Merritt TA, Hallman M, Bloom BT, et al. Prophylactic treatment of very premature infants with human surfactant. N Engl J Med 1986;315:785-90. 7. Raju TNK, Vidyasagar D, Bhat R, et al. Double-blind controlled trial of single dose treatment with bovine surfactant in severe hyaline membrane disease. Lancet 1987;1:651-6. 8. Horbar JD, Soll RF, Sutherland JM, et al. A multicenter randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome. N Engl J Med 1989;320:959-65. 9. Lang M J, Hall RT, Reddy NS, et al. A controlled trial of human surfactant replacement therapy for severe respiratory distress syndrome in very low birth weight infants. J P~DIATR 1990;116:295-300. 10. Milner A, Vyas H, Hopkins I, et al. Effects of artificial surfactant on lung function and blood gases in idiopathic respiratory distress syndrome. Arch Dis Child 1983;58:458-61. 11. Milner A, Vyas H, Hopkins I, et al. Effects of exogenous surfactant on total respiratory system compliance. Arch Dis Child 1984;59:369-71. 12. Mannino F, Merritt AT, Hallman M, et al. Surfactant treatment in neonates with severe RDS improves oxygenation without improving dynamic lung compliance [Abstract]. Pediatr Res 1985;19:409A. 13. Jobe A, Ikegami M, Glatz T, et al. Duration and characteristics of treatment of premature lambs with natural surfactant. J Clin Invest 1981;67:370-5. 14. Vidyasagar D, Maeta H, Raju TNK, et al. Bovine surfactant (surfactant TA) therapy in immature baboons with hyaline membrane disease. Pediatrics 1985;75:1132-6. 15. Bhat R, Dziedzic K, Bhutani VK, Vidyasager D. Effect of single dose surfactant on pulmonary function. Crit Care Med 1990;18:590-5. 16. Couser R J, Ferrara TB, Ebert J, et al. Effects of exogenous surfactant therapy on dynamic compliance during mechanical breathing in preterm infants with hyaline membrane disease. J PED~ATR 1990;116:119-24. 17. Davis JM, Veness-Meehan K, Notter RH, et al. Changes in pulmonary mechanics after the administration of surfactant to infants with respiratory distress syndrome. N Engl J Med 1988;319:476-9. 18. Long W, Thompson T, Sundell H, et al. Effects of two rescue
The Journal of Pediatrics February 1992
19.
20.
21. 22.
23. 24.
25.
26.
27.
28.
29.
30.
doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome. J PEt~IATR 1991; 118:595-605. Long W, Corbet A, Cotton R, et al., the American Exosurf Neonatal Study Group I, and the Canadian Exosurf Neonatal Study Group. A controlled trial of synthetic surfactant in infants weighing 1250 g or more with respiratory distress syndrome. N Engl J Med 1991;325:1696-703. Bhutani VK, Sivieri EM, Abbasi S, Shaffer TM. Evaluation of neonatal pulmonary mechanics: two factor least mean-square analysis technique. Pediatr Pulmonol 1988;4:150-8. Gerhardt T, Bancalari E. Chest wall compliance in fnll-term and premature infants. Acta Pediatr Scand 1980;59:359-64. LeSnuef PN, Lopes JM, England S J, et al. Influence of chest wall distortion on esophageal pressure. J Appl Physiol 1983;55: 353-8. Heldt GP, Mcllroy MB. Distortion of chest wall and work of diaphragm in preterm infants. J Appl Physiol 1987;62:164-9. Sly PD, Brown KA, Bates JHT, et al. Noninvasive determination of respiratory mechanics during mechanical ventilation of neonates: a review of current and future techniques. Pediatr Pulmonol 1988;4:39-47. Bhutani VK. Pulmonary function profile: computer analysis and pulmonary graphics. In: Bhutani VK, Shaffer TH, Vidyasager D, eds. Neonatal pulmonary function testing: physiological, technical and clinical considerations. Ithaca, N.Y.: Perinatology Press, 1988;13-33. Mammel MC, Fisher JB, Bing DR, et al. Effect of spontaneous and mechanical breathing on dynamic lung mechanics in hyaline membrane disease. Pediatr Pulmonol 1990;8:222-5. Sivieri E, Abbasi S, Bhutani VK. On-line pulmonary graphics for assistance in the manual ventilation of neonates. In: Gennser G, Marsal K, Svenninsen N, Lindstrom K, eds. Fetal and neonatal physiological measurements, vol III. Malmo, Sweden: Department of Obstetrics and Gynecology, Malmo General Hospital, 1989;425-9. Gerhardt T, Hehre D, Feller R, et al. Pulmonary mechanics in normal infants and young children during first 5 years of life. Pediatr Pulmonol 1987;3:309-16. Abbasi S, Bhutani VK. Pulmonary mechanics and energetics of normal, non-ventilated low birth weight infants. Pediatr Pulmonol 1990;8:89-95. McCann EM, Goldman SL, Brady JP. Pulmonary function in the sick newborn infant. Pediatr Res 1987;21:313-25.