Biol. Neonate 31: 245 251 (1977)
Oxygen Consumption of the Newborn Rabbit Treated with Pulmonary Surfactant1 A. Wallin, R. Burgoyne and G. Enhorning Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ont.
Key Words. Surfactant • Oxygen consumption • Neonatal survival ■Pharyngeal deposition of
surfactant
Pulmonary surfactant (SA), deposited in the upper airways of the prematurely delivered rabbit, facilitates transition to extra-uterine life (3- 5). If the deposition is made prior to the first breath, the SA will be in the air-liquid interfaces, moving down the airways to the alveolar sacs. The SA is then evenly distributed and is concentrated at a site where it can exert an optimal effect. This administration makes lung expansion easier, augments pulmonary stability, and prevents air trapping. Survival of the prematurely delivered rabbit is significantly 1 This work was supported by The Canadian Medical Research Council (grant No. MA-4497).
improved. This is undoubtedly the ultimate proof of the beneficial effect the SA deposition has but, since an increased pulmonary gas ex change is likely to be the cause of this effect, another way of assessing the value of SA depo sition would be to determine the oxygen con sumption of the neonate. This is a report on such determinations following SA treatment of newborn rabbits delivered on the 27th, 28th, 29th, or 30th day of gestation. The study was primarily planned to assess, with a new parameter, the beneficial effect the SA deposition might have on the premature neonate. However, it was also intended as a check of the possible harm the treatment might
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Abstract. A method is described for measuring oxygen consumption of small animals. It was used for 151 newborn rabbits delivered on the 27th, 28th, 29th, and 30th day of gestation. Half of the neonates were given a pharyngeal deposition of a concentrated surfactant (SA) suspension prior to their first breath. The remaining neonates served as controls. The survival rate among the immature rabbits treated with SA was significantly higher. The treatment did not affect oxygen consumption in any age-group. With increasing maturity, the neonates consumed more oxygen, and the controls delivered on the 30th day of gestation consumed 29.6 ± SEM 4.2 ml oxygen per kilogram and minute.
Wallin/Buigoyne/Enhorning
Fig. 1. System used for studying the oxygen con sumption of 4 animals simultaneously. The chamber in which the animal is enclosed is in a thermostatic bath. Oxygen content in chamber (only one shown) remains unaltered since carbon dioxide produced is absorbed and oxygen consumed is replaced from spirometer to the right containing pure oxygen. Each spirometer consists of a thin-walled transparent cylinder open at
the lower end and, through a spiralled nylon tubing from the upper end, communicating with its chamber. The spirometer is kept vertical by being supported by a styrofoam ring and a lead weight at its lower end. Since oxygen consumed is replaced by water, con sumption is easily read. When oxygen in a spirometer has been consumed, it is replaced from a syringe.
cause if given to neonates who were in no need of supplementary SA because their lungs were fully mature. To augment the harmful effect the SA might have, the newborns were given no extra oxygen, and to augment their require ment of this gas they were studied at an ambient temperature of only 32 °C. Under these conditions we were able to confirm our previous finding that SA deposition before the first breath significantly improved survival of premature rabbits, but had no effect on animals
delivered close to term. We also found that the oxygen consumption among the surviving neo nates was not significantly altered by the ad ministered SA. It was felt, however, that the treatment when given to the premature neonate ought to be tested also under more favourable conditions, simulating those present in an incu bator of a premature nursery. Under such cir cumstances the untreated controls should also have a better chance to survive. Consequently, in a second series, the oxygen consumption was
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246
247
Oxygen Consumption and Surfactant
Material and Methods As described in previous reports (3—5), the SA suspension was obtained by centrifuging the lungwash from an adult rabbit at l,000g and 4 °C for 1 h. The white pellet obtained was resuspended in an equal volume of supernatant and stored at - 2 0 °C until used. The surface activity of such a suspension did not deteriorate by freezing, as demonstrated with the pulsating bubble technique (1). The total number of newborn rabbits studied was 151 from 38 does. Of these, 119 newborns from 30 does constituted the first series, examined at 32 °C and 20 % oxygen. The second series, examined at 35 °C and in 40 % oxygen, consisted of 32 newborns from 8 does, all on the 28th day of gestation. The rabbits were delivered by hysterotomy when there was approximately 4 h left of the 27 th, 28th, 29th, or 30th day of gestation. A rapid intravenous injection of 250 mg phénobarbital made it possible to incise the abdominal wall and clamp the uterine arteries within 1 min from starting the injection. 1 doe had only 3 fetuses, 2 of which were given treatment and 1 served as control. Otherwise, 1 at a time, 4 fetuses were delivered from each doe and handled as follows: to prevent them from breathing, their chests were held squeezed while fluid in the pharynx was sucked away. Every other animal was then treated with 100 ul (in second series, 50 mO of SA suspension deposited in the pharynx. They were then stimulated to breathe, as were the other newborns serving as controls. Until all 4 rabbits to be studied from a litter had been delivered and were ready for measurement of their oxygen consumption, they were kept in an environment where temperature and oxygen concen tration were controlled. For measuring oxygen consumption, a system was developed which made it possible to study several animals simultaneously (fig. 1). We used it for 4 newborns from each litter, 2 treated and 2 controls. Each neonate was enclosed in an airtight chamber containing room air or, for the second series, 40 % oxygen. To ensure that the carbon dioxide produced
by the animal was absorbed continuously by potassi um hydroxide pellets, the air inside the chamber was kept circulating by a small fan. Lead weights in the chambers caused them to stay under water in a bath which was thermostatically controlled at 32 °C (35 °C in the second series). Any oxygen consumed by the animal was replaced via a narrow nylon tube which gave communication with a small spirometer containing pure oxygen. This made it easy to measure the oxygen consumption over a certain period of time. We allowed 15 min for temper ature equilibration and then measured the consump tion during the following five 15-min periods, i.e. until the animals had been in the chambers for 90 min. As soon as they had been taken out, we attempted to obtain a blood sample from the jugular vein. If the animal was alive, we were successful in most instances, and could determine pH, using a Radiometer glass electrode instrument.
Results
Survival rate was significantly higher (p < 0.005) among the treated neonates delivered on the 27th day of gestation. Ten of the 14 treated animals were alive at the end of the experiment, but only 1 of the 14 controls. In the two groups of animals delivered on the 28th day of gestation, there was a higher survival rate among treated neonates (36 of 38) than among controls (29 of 38), but the difference was not statistically significant (p > 0.05). Figure 2 shows how the survival was distributed among the two 28th-day series. It is also seen that the survival rate was high in the two more mature age-groups, both with and without treatment. The oxygen consumption of the only surviv ing 27th-day control was very low when com pared with the average consumption of treated animals of that age (table I; fig. 3). Otherwise, in the first series there was no significant difference in oxygen consumption between treated animals and controls of the same gesta tional age. Nor was there any significant change
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measured when the amount of SA deposited was optimal, when the neonate was breathing 40 % oxygen and was in an ambient tempera ture of 35 °C.
46--60 61--75 76--90 16--90
2.2 6.0 6.7 3.3 8.9 5.4 -
11.4 ± 1.5 10.8 + 1.1 11.6 + 1.1 11.7 + 0.9 11.7 ± 1.1 11.4 ± 0.9 7.14 ± 0.04*
12.3 12.6 14.1 12.7 12.7 12.9 7.26
11.8 11.9 11.6 11.8 11.3 11.7 7.13
± 1.6 + 1.2 + 0.9 ± 1.2 ± 1.2 ± 0.9 + 0.03
± 1.1 ± 1.2 + 0.8 + 0.7 ± 0.6 ± 0.6
+
10.7 11.9 11.8 11.6 10.2 11.3 7.18
± 1.6 + 3.0 + 0.8 + 0.5 ± 0.5
19.8 19.8 17.5 15.0 14.7 ± 17.6 + 0.056 7.25
± 2.7 ± 2.5 + 2.3 ± 2.0 ± 2.7 ± 2.1
±
Consumption and pH (mean ± SE) went up with increasing maturity, n = Number of animals; C = controls. First series: 32 °C, 20 % oxygen, 100 pi SA. Second series: 35 °C, 40 % oxygen, 50 pi SA. n = 7. n = 18. n = 14. n = 12. n = 13.
22.2 21.3 19.3 17.8 18.6 20.6 7.26
± 2.9 + 2.9 + 2.7 ± 2.6 ± 3.5 + 2.6 + 0.02
30th1 ---------------------------SA, n = 10 C, n = 10 32.5 31.2 25.6 23.7 24.4 27.5 7.31
+ 2.9 ± 3.1 + 4.1 ± 4.3 + 4.4 + 3.4 + 0.02
33.9 33.0 27.4 26.5 27.3 29.6 7.31
± 3.5 ± 3.0 ± 4.2 ± 5.0 ± 5.6 ± 4.2 ± 0.02
Wallin/Burgoync/Enhorning
1 2 5 4 5 6 1
±
CO o O
PH
+ 1.0 ± 0.8 + 0.8 + 0.9 ± 1.0 ± 0.8
29th1 -----------------------------SA, n = 14 C, n = 1 2
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6.5 9.2 9.8 10.2 11.0 9.3 7.10
28th2*45 -----------------------------SA, n = 1 6 C, n = 14
C'J O o
16--30
31--45
28th1 -----------------------------SA, n = 20 C, n = 1 5
oo ©
27th*1 -----------------------------SA, n = 10 C, n = 1
C-l O o
Time interval min
248
Table I. Oxygen consumption and pH of the four age-groups studied in the first series and of the 28th-day neonates of the second series
Oxygen Consumption and Surfactant
249
7.4 -
•
• • o
it
7.3 I '
° * O
7.2
•
o
i
°* *o
• * 0 %o * *
o
•
A o * • O
•
0
•
•
•
AA
4
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a
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£
°
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7.0 «0
A
S A - t r e a t e d ■ First s e r ie s C o n tro ls o S A -tre a te d -S e co n d s e r ie s » C o n t r o ls
o •
6 .9
bo
A
CD
pH
o
o* o [
1
1
1
10
20
30
40
i
i
50
60
Fig. 2. Distribution of material in first (*) and second (**) series. On the 27th day, survival was significantly higher among treated animals.
Fig. 3. Oxygen consumption of surviving newborns in first (*) and second (**) series. Mean ± SE. Fig. 4. Jugular vein pH plotted against oxygen consumption.
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O xyg en c o n s u m p tio n , m l/ k g / m in
in consumption during the five 15-min periods of measurement. On the other hand, it was clearly noticeable that the oxygen consump tion, measured in milliliters per kilogram body weight per minute rose with gestational age. The increase in consumption from the 28th to the 30th day was highly significant (p < 0.001) among treated as well as control animals. The low oxygen consumption of the most premature neonates resulted in the develop ment of severe acidosis but, with the greater consumption of oxygen accompanying increas ing maturity, pH approached more normal values (table I; fig. 4). The pH observed at the 30th day was higher than that of the 28th day of the first series (p < 0.001). In none of the age-groups examined did the pH of the treated animals differ significantly from that of the controls. In the second series, the oxygen consump tion was not greater than it was on the 28th day of the first series, yet the pH of the treated animals was higher (p < 0 .0 1 ). This lesser tendency to develop acidosis, noted in the second series, was perhaps due to the higher ambient temperature which reduced the oxygen requirement.
Discussion
Previous studies have demonstrated that SA, deposited in the pharynx of premature rabbit neonates immediately after delivery, results in an improved chance of survival (3 -5 ). In plan ning those studies, it was felt to be essential that the deposition be made prior to the first breath and that the SA be given in an optimal quantity. The requisite that the SA has to be deposited prior to the first breath must be adhered to. Only then would the SA be in the pulmonary air-liquid interfaces, reducing the
resistance surface tension offers to air expan sion. On the other hand, it would seem from the present study that the volume of SA sus pension administered is not so critical. Al though the amount given was double that found to be optimal, it was still highly effec tive. If SA were to be used in the prematurely delivered human infant as a prophylaxis against the respiratory distress syndrome, it would be difficult to avoid using a dose greater than the optimal, since the size of the fetus can only be roughly estimated during delivery. This would seem to be acceptable, however, since a dose double that of the optimal for the 27th-day newborn rabbit resulted in no damage, but in a dramatically increased survival rate. If SA were to be used clinically, not only would it often be given in a higher dose than was actually required, it would also be used for infants who really did not need SA but were given it because they were thought to be more immature than they really were. This gives some importance to our finding that, at least in the rabbit, SA does not cause any immediate harm, even when given to mature neonates. The most mature animals of this study, those with a gestational age of 30 days, con sumed no less than about 30 ml oxygen per kilogram body weight per minute. This is a consumption more than twice that reported by Hardman et al. (6) for the term rabbit. This difference can probably be explained by the fact that we kept the animals in a cooler environment and, as demonstrated by Hull (7), consumption of oxygen in the rabbit neonate increases greatly with lowering of the ambient temperature. The more premature the newborn animal, the greater the stress of a low temperature and the less the ability to maintain an adequate oxygen uptake. SA deposition helped the pre mature rabbits to survive, but among those
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Wallin/Burgoyne/Enhorning
250
Oxygen Consumption and Surfactant
staying alive, the oxygen consumption was low among control as well as treated animals. This indicates that the lungs were immature also in other respects than by being unable to release adequate quantities of SA. Their function could, for instance, have been hampered by an excessive quantity of airway fluid, the absorp tion of which takes several hours (6). The low oxygen consumption observed in the premature neonate may also have been due to causes other than inadequate lung expansion. It is conceivable that the resistance to pulmo nary blood flow was greater, causing a right-toleft shunt through the foramen ovale and the ductus arteriosus. A poor delivery of oxygen to tissues may also have been due to a diminished peripheral blood flow, and to the fetal erythro cytes having a high affinity for oxygen because of their low concentration of adult haemoglo bin and of 2,3-diphosphoglycerate (2).
251
2 Delivoria-Papadopoulos, M.; Roncevic, N.P., and Oski, F.A.: Postnatal changes in oxygen transport of term, premature, and sick infants: the role of red cell 2,3-diphosphoglycerate and adult hemo globin. Pediat. Res. 5: 235-245 (1971). 3 Enhorning, G.; Grossmann, G., and Robertson, B.: Tracheal deposition of surfactant before the first breath. Am. Rev. resp. Dis. 107: 921-927 (1973). 4 Enhorning, G.; Grossmann, G., and Robertson, B.: Pharyngeal deposition of surfactant in the prema ture rabbit fetus. Biol. Neonate 22: 126-132 (1973). 5 Enhorning, G.; Robertson, B.; Milne, E., and Wag ner, R.: Radiological evaluation of the premature rabbit neonate after pharyngeal deposition of sur factant. Am. J. Obstct. Gynec. 121: 475-480 (1975). 6 Hardman, M.J.; Hey, E.N., and Hull, D.: The effect of prolonged cold exposure on heat production in new-born rabbits. J. Physiol., Lond. 205: 39-50 (1969). 7 Hull, D.: Oxygen consumption and body tempera ture of new-born rabbits and kittens exposed to cold. J. Physiol., Lond. 177: 192-202 (1965).
References Dr. Goran Enhorning, Room 7263, Medical Sciences Building, University of Toronto, Toronto, Ont. M5S 1A8 (Canada)
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1 Adams, F.H. and Enhorning, G.: Surface properties of lung extracts. I. A dynamic alveolar model. Acta physiol, scand. 68: 23-27 (1966).
Oxygen Consumption of the Newborn Rabbit Treated with Pulmonary Surfactant1 A. Wallin, R. Burgoyne and G. Enhorning Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ont.
Key Words. Surfactant • Oxygen consumption • Neonatal survival ■Pharyngeal deposition of
surfactant
Pulmonary surfactant (SA), deposited in the upper airways of the prematurely delivered rabbit, facilitates transition to extra-uterine life (3- 5). If the deposition is made prior to the first breath, the SA will be in the air-liquid interfaces, moving down the airways to the alveolar sacs. The SA is then evenly distributed and is concentrated at a site where it can exert an optimal effect. This administration makes lung expansion easier, augments pulmonary stability, and prevents air trapping. Survival of the prematurely delivered rabbit is significantly 1 This work was supported by The Canadian Medical Research Council (grant No. MA-4497).
improved. This is undoubtedly the ultimate proof of the beneficial effect the SA deposition has but, since an increased pulmonary gas ex change is likely to be the cause of this effect, another way of assessing the value of SA depo sition would be to determine the oxygen con sumption of the neonate. This is a report on such determinations following SA treatment of newborn rabbits delivered on the 27th, 28th, 29th, or 30th day of gestation. The study was primarily planned to assess, with a new parameter, the beneficial effect the SA deposition might have on the premature neonate. However, it was also intended as a check of the possible harm the treatment might
Downloaded by: East Carolina University - Laupus Library 150.216.68.200 - 1/15/2019 11:06:45 AM
Abstract. A method is described for measuring oxygen consumption of small animals. It was used for 151 newborn rabbits delivered on the 27th, 28th, 29th, and 30th day of gestation. Half of the neonates were given a pharyngeal deposition of a concentrated surfactant (SA) suspension prior to their first breath. The remaining neonates served as controls. The survival rate among the immature rabbits treated with SA was significantly higher. The treatment did not affect oxygen consumption in any age-group. With increasing maturity, the neonates consumed more oxygen, and the controls delivered on the 30th day of gestation consumed 29.6 ± SEM 4.2 ml oxygen per kilogram and minute.
Wallin/Buigoyne/Enhorning
Fig. 1. System used for studying the oxygen con sumption of 4 animals simultaneously. The chamber in which the animal is enclosed is in a thermostatic bath. Oxygen content in chamber (only one shown) remains unaltered since carbon dioxide produced is absorbed and oxygen consumed is replaced from spirometer to the right containing pure oxygen. Each spirometer consists of a thin-walled transparent cylinder open at
the lower end and, through a spiralled nylon tubing from the upper end, communicating with its chamber. The spirometer is kept vertical by being supported by a styrofoam ring and a lead weight at its lower end. Since oxygen consumed is replaced by water, con sumption is easily read. When oxygen in a spirometer has been consumed, it is replaced from a syringe.
cause if given to neonates who were in no need of supplementary SA because their lungs were fully mature. To augment the harmful effect the SA might have, the newborns were given no extra oxygen, and to augment their require ment of this gas they were studied at an ambient temperature of only 32 °C. Under these conditions we were able to confirm our previous finding that SA deposition before the first breath significantly improved survival of premature rabbits, but had no effect on animals
delivered close to term. We also found that the oxygen consumption among the surviving neo nates was not significantly altered by the ad ministered SA. It was felt, however, that the treatment when given to the premature neonate ought to be tested also under more favourable conditions, simulating those present in an incu bator of a premature nursery. Under such cir cumstances the untreated controls should also have a better chance to survive. Consequently, in a second series, the oxygen consumption was
Downloaded by: East Carolina University - Laupus Library 150.216.68.200 - 1/15/2019 11:06:45 AM
246
247
Oxygen Consumption and Surfactant
Material and Methods As described in previous reports (3—5), the SA suspension was obtained by centrifuging the lungwash from an adult rabbit at l,000g and 4 °C for 1 h. The white pellet obtained was resuspended in an equal volume of supernatant and stored at - 2 0 °C until used. The surface activity of such a suspension did not deteriorate by freezing, as demonstrated with the pulsating bubble technique (1). The total number of newborn rabbits studied was 151 from 38 does. Of these, 119 newborns from 30 does constituted the first series, examined at 32 °C and 20 % oxygen. The second series, examined at 35 °C and in 40 % oxygen, consisted of 32 newborns from 8 does, all on the 28th day of gestation. The rabbits were delivered by hysterotomy when there was approximately 4 h left of the 27 th, 28th, 29th, or 30th day of gestation. A rapid intravenous injection of 250 mg phénobarbital made it possible to incise the abdominal wall and clamp the uterine arteries within 1 min from starting the injection. 1 doe had only 3 fetuses, 2 of which were given treatment and 1 served as control. Otherwise, 1 at a time, 4 fetuses were delivered from each doe and handled as follows: to prevent them from breathing, their chests were held squeezed while fluid in the pharynx was sucked away. Every other animal was then treated with 100 ul (in second series, 50 mO of SA suspension deposited in the pharynx. They were then stimulated to breathe, as were the other newborns serving as controls. Until all 4 rabbits to be studied from a litter had been delivered and were ready for measurement of their oxygen consumption, they were kept in an environment where temperature and oxygen concen tration were controlled. For measuring oxygen consumption, a system was developed which made it possible to study several animals simultaneously (fig. 1). We used it for 4 newborns from each litter, 2 treated and 2 controls. Each neonate was enclosed in an airtight chamber containing room air or, for the second series, 40 % oxygen. To ensure that the carbon dioxide produced
by the animal was absorbed continuously by potassi um hydroxide pellets, the air inside the chamber was kept circulating by a small fan. Lead weights in the chambers caused them to stay under water in a bath which was thermostatically controlled at 32 °C (35 °C in the second series). Any oxygen consumed by the animal was replaced via a narrow nylon tube which gave communication with a small spirometer containing pure oxygen. This made it easy to measure the oxygen consumption over a certain period of time. We allowed 15 min for temper ature equilibration and then measured the consump tion during the following five 15-min periods, i.e. until the animals had been in the chambers for 90 min. As soon as they had been taken out, we attempted to obtain a blood sample from the jugular vein. If the animal was alive, we were successful in most instances, and could determine pH, using a Radiometer glass electrode instrument.
Results
Survival rate was significantly higher (p < 0.005) among the treated neonates delivered on the 27th day of gestation. Ten of the 14 treated animals were alive at the end of the experiment, but only 1 of the 14 controls. In the two groups of animals delivered on the 28th day of gestation, there was a higher survival rate among treated neonates (36 of 38) than among controls (29 of 38), but the difference was not statistically significant (p > 0.05). Figure 2 shows how the survival was distributed among the two 28th-day series. It is also seen that the survival rate was high in the two more mature age-groups, both with and without treatment. The oxygen consumption of the only surviv ing 27th-day control was very low when com pared with the average consumption of treated animals of that age (table I; fig. 3). Otherwise, in the first series there was no significant difference in oxygen consumption between treated animals and controls of the same gesta tional age. Nor was there any significant change
Downloaded by: East Carolina University - Laupus Library 150.216.68.200 - 1/15/2019 11:06:45 AM
measured when the amount of SA deposited was optimal, when the neonate was breathing 40 % oxygen and was in an ambient tempera ture of 35 °C.
46--60 61--75 76--90 16--90
2.2 6.0 6.7 3.3 8.9 5.4 -
11.4 ± 1.5 10.8 + 1.1 11.6 + 1.1 11.7 + 0.9 11.7 ± 1.1 11.4 ± 0.9 7.14 ± 0.04*
12.3 12.6 14.1 12.7 12.7 12.9 7.26
11.8 11.9 11.6 11.8 11.3 11.7 7.13
± 1.6 + 1.2 + 0.9 ± 1.2 ± 1.2 ± 0.9 + 0.03
± 1.1 ± 1.2 + 0.8 + 0.7 ± 0.6 ± 0.6
+
10.7 11.9 11.8 11.6 10.2 11.3 7.18
± 1.6 + 3.0 + 0.8 + 0.5 ± 0.5
19.8 19.8 17.5 15.0 14.7 ± 17.6 + 0.056 7.25
± 2.7 ± 2.5 + 2.3 ± 2.0 ± 2.7 ± 2.1
±
Consumption and pH (mean ± SE) went up with increasing maturity, n = Number of animals; C = controls. First series: 32 °C, 20 % oxygen, 100 pi SA. Second series: 35 °C, 40 % oxygen, 50 pi SA. n = 7. n = 18. n = 14. n = 12. n = 13.
22.2 21.3 19.3 17.8 18.6 20.6 7.26
± 2.9 + 2.9 + 2.7 ± 2.6 ± 3.5 + 2.6 + 0.02
30th1 ---------------------------SA, n = 10 C, n = 10 32.5 31.2 25.6 23.7 24.4 27.5 7.31
+ 2.9 ± 3.1 + 4.1 ± 4.3 + 4.4 + 3.4 + 0.02
33.9 33.0 27.4 26.5 27.3 29.6 7.31
± 3.5 ± 3.0 ± 4.2 ± 5.0 ± 5.6 ± 4.2 ± 0.02
Wallin/Burgoync/Enhorning
1 2 5 4 5 6 1
±
CO o O
PH
+ 1.0 ± 0.8 + 0.8 + 0.9 ± 1.0 ± 0.8
29th1 -----------------------------SA, n = 14 C, n = 1 2
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6.5 9.2 9.8 10.2 11.0 9.3 7.10
28th2*45 -----------------------------SA, n = 1 6 C, n = 14
C'J O o
16--30
31--45
28th1 -----------------------------SA, n = 20 C, n = 1 5
oo ©
27th*1 -----------------------------SA, n = 10 C, n = 1
C-l O o
Time interval min
248
Table I. Oxygen consumption and pH of the four age-groups studied in the first series and of the 28th-day neonates of the second series
Oxygen Consumption and Surfactant
249
7.4 -
•
• • o
it
7.3 I '
° * O
7.2
•
o
i
°* *o
• * 0 %o * *
o
•
A o * • O
•
0
•
•
•
AA
4
7.1
a
0«
O •
O
o o
• A
£
°
O
0*
* o
•
7.0 «0
A
S A - t r e a t e d ■ First s e r ie s C o n tro ls o S A -tre a te d -S e co n d s e r ie s » C o n t r o ls
o •
6 .9
bo
A
CD
pH
o
o* o [
1
1
1
10
20
30
40
i
i
50
60
Fig. 2. Distribution of material in first (*) and second (**) series. On the 27th day, survival was significantly higher among treated animals.
Fig. 3. Oxygen consumption of surviving newborns in first (*) and second (**) series. Mean ± SE. Fig. 4. Jugular vein pH plotted against oxygen consumption.
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O xyg en c o n s u m p tio n , m l/ k g / m in
in consumption during the five 15-min periods of measurement. On the other hand, it was clearly noticeable that the oxygen consump tion, measured in milliliters per kilogram body weight per minute rose with gestational age. The increase in consumption from the 28th to the 30th day was highly significant (p < 0.001) among treated as well as control animals. The low oxygen consumption of the most premature neonates resulted in the develop ment of severe acidosis but, with the greater consumption of oxygen accompanying increas ing maturity, pH approached more normal values (table I; fig. 4). The pH observed at the 30th day was higher than that of the 28th day of the first series (p < 0.001). In none of the age-groups examined did the pH of the treated animals differ significantly from that of the controls. In the second series, the oxygen consump tion was not greater than it was on the 28th day of the first series, yet the pH of the treated animals was higher (p < 0 .0 1 ). This lesser tendency to develop acidosis, noted in the second series, was perhaps due to the higher ambient temperature which reduced the oxygen requirement.
Discussion
Previous studies have demonstrated that SA, deposited in the pharynx of premature rabbit neonates immediately after delivery, results in an improved chance of survival (3 -5 ). In plan ning those studies, it was felt to be essential that the deposition be made prior to the first breath and that the SA be given in an optimal quantity. The requisite that the SA has to be deposited prior to the first breath must be adhered to. Only then would the SA be in the pulmonary air-liquid interfaces, reducing the
resistance surface tension offers to air expan sion. On the other hand, it would seem from the present study that the volume of SA sus pension administered is not so critical. Al though the amount given was double that found to be optimal, it was still highly effec tive. If SA were to be used in the prematurely delivered human infant as a prophylaxis against the respiratory distress syndrome, it would be difficult to avoid using a dose greater than the optimal, since the size of the fetus can only be roughly estimated during delivery. This would seem to be acceptable, however, since a dose double that of the optimal for the 27th-day newborn rabbit resulted in no damage, but in a dramatically increased survival rate. If SA were to be used clinically, not only would it often be given in a higher dose than was actually required, it would also be used for infants who really did not need SA but were given it because they were thought to be more immature than they really were. This gives some importance to our finding that, at least in the rabbit, SA does not cause any immediate harm, even when given to mature neonates. The most mature animals of this study, those with a gestational age of 30 days, con sumed no less than about 30 ml oxygen per kilogram body weight per minute. This is a consumption more than twice that reported by Hardman et al. (6) for the term rabbit. This difference can probably be explained by the fact that we kept the animals in a cooler environment and, as demonstrated by Hull (7), consumption of oxygen in the rabbit neonate increases greatly with lowering of the ambient temperature. The more premature the newborn animal, the greater the stress of a low temperature and the less the ability to maintain an adequate oxygen uptake. SA deposition helped the pre mature rabbits to survive, but among those
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staying alive, the oxygen consumption was low among control as well as treated animals. This indicates that the lungs were immature also in other respects than by being unable to release adequate quantities of SA. Their function could, for instance, have been hampered by an excessive quantity of airway fluid, the absorp tion of which takes several hours (6). The low oxygen consumption observed in the premature neonate may also have been due to causes other than inadequate lung expansion. It is conceivable that the resistance to pulmo nary blood flow was greater, causing a right-toleft shunt through the foramen ovale and the ductus arteriosus. A poor delivery of oxygen to tissues may also have been due to a diminished peripheral blood flow, and to the fetal erythro cytes having a high affinity for oxygen because of their low concentration of adult haemoglo bin and of 2,3-diphosphoglycerate (2).
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2 Delivoria-Papadopoulos, M.; Roncevic, N.P., and Oski, F.A.: Postnatal changes in oxygen transport of term, premature, and sick infants: the role of red cell 2,3-diphosphoglycerate and adult hemo globin. Pediat. Res. 5: 235-245 (1971). 3 Enhorning, G.; Grossmann, G., and Robertson, B.: Tracheal deposition of surfactant before the first breath. Am. Rev. resp. Dis. 107: 921-927 (1973). 4 Enhorning, G.; Grossmann, G., and Robertson, B.: Pharyngeal deposition of surfactant in the prema ture rabbit fetus. Biol. Neonate 22: 126-132 (1973). 5 Enhorning, G.; Robertson, B.; Milne, E., and Wag ner, R.: Radiological evaluation of the premature rabbit neonate after pharyngeal deposition of sur factant. Am. J. Obstct. Gynec. 121: 475-480 (1975). 6 Hardman, M.J.; Hey, E.N., and Hull, D.: The effect of prolonged cold exposure on heat production in new-born rabbits. J. Physiol., Lond. 205: 39-50 (1969). 7 Hull, D.: Oxygen consumption and body tempera ture of new-born rabbits and kittens exposed to cold. J. Physiol., Lond. 177: 192-202 (1965).
References Dr. Goran Enhorning, Room 7263, Medical Sciences Building, University of Toronto, Toronto, Ont. M5S 1A8 (Canada)
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1 Adams, F.H. and Enhorning, G.: Surface properties of lung extracts. I. A dynamic alveolar model. Acta physiol, scand. 68: 23-27 (1966).
