(Received 1 November 1950)

Transcription

1 283 J. Physiol. (I95I) II4, THE EFFECT OF INHALATION OF HIGH AND LOW OXYGEN NCENTRATIONS ON THE RESPIRATION OF THE NEWBORN INFANT BY K. W. CROSS AND PAMELA WARNER From the Physiology Department and Paediatric Unit, St Mary's Hospital Medical School, London (Received 1 November 195) Knowledge of the stages of development of reflex responses in the developing foetus or infant is clearly of great importance in the management of the newborn infant. The respiratory reflexes are of particular interest, and we have attempted here to establish whether or not the responses of the infant to high and low oxygen concentrations suggest that the carotid and aortic chemoreceptors are active shortly after birth. There is some theoretical evidence to suggest that this may not be so. Clark (1935) has brought forward evidence to suggest that the baroceptors of the carotid sinus and aortic arch are not active in the newborn cat and dog, and this is surprising in view of the early completion (histologically) of innervation of the carotid sinus compared with the later development of the carotid body (Boyd, 195). Dripps & mroe (1947), in their careful work on the adult human subject, found that there was an initial drop in the minute ventilation volume when high concentrations of oxygen were inhaled, and they also found that the volume increased when the inspired air contains 15 % oxygen or less. Howard & Bauer (195), however, working with newborn babies, report that the minute ventilation volume rises with high concentrations of oxygen and falls when the oxygen percentage of the inspired air is lowered. To obtain clear-cut evidence on this matter from babies, who are notoriously active subjects, is a matter of great difficulty, and for this reason full details of the technique used are stated. Indirect evidence alone will be available from babies, and the concept of 'physiological denervation by giving 1 % oxygen' as outlined by Dripps & mroe (1947) has been used. These authors suggest that with 1% oxygen in the inspired air there will be no anoxic drive of the respiratory centre from the aortic and carotid chemoreceptors. METHOD The plethysmograph described previously (Cross, 1949) was used. This had been modified by changing the sponge-core rubber seal on the lid of the brass box for a mercury seal (Fig. 1), because PH. CXIV. 19

2 284 K. W. CROSS AND PAMELA WARNER the rubber tended to perish and leak; also, the baby could be released from the plethysmograph even more quickly than when the lid was held down with paper-clips. It was necessary to be able to supply any gas mixture to the baby while it slept and while a continuous record of the respiration was being made, and to ensure that any changes which occurred were due to an effect of the gas itself and were not caused by a disturbance arising from the method of application. A mask was designed which is also illustrated in Fig. 1. The gas passed from cylinders through a reducing valve and Heidbrink flow-meter to a Marriott's bottle, where it was partially humidified by water at room temperature. From the bottle a further 3 ft. of rubber tubing led to the mask, and here a baffle plate was placed between the gas inlet and the face of the baby. The direction of flow of the mixture was from the forehead to the chin of the baby. So that the mask could be easily applied, the pneumatic cuff which sealed the baby in the plethysmograph was turned upside down, and the tube inflating it was passed through the wall of the plethysmograph. No attempt was made to make the mask absolutely airtight at its junction with the lid of the plethysmograph, for, as gas was flowing through it at 5 I./min., it was unlikely that there would be serious dilution of the air in the mask by the outside air, as any leakage would be.outwards. Air or oxygen e llmez~~~~~~~~~~~~~~culry reservoir Fig. 1. Diagrammatic longitudinal section of head end of the plethysmograph showing the mercury seal for the lid and the mask used to supply Oz to the infant. It was necessary to establish a rate of gas flow which was sufficiently fast to prevent the infant re-breathing its own 2 and yet sufficiently slow as not to disturb the infant by the draught of air. Tests with air from a compressed air cylinder established that a rate of flow of 5 1./min. (as measured on the oxygen scale of Heidbrink flow-meter) satisfied these conditions. Analysis, in Haldane gas analysis apparatus, of the air from above the forehead of the baby and from below the nose showed no increase in 2 in the 'forehead' specimen, but the specimen from below the nose showed up to -2 % 2, depending upon the phase of respiration at which the specimen was collected. The infants continued to sleep quietly in these circumstances. In a comparison of minute ventilation volumes of sleeping babies for the 5 min. before, and the 5 min. during which air was supplied by this method, it was found in a series of 12 observations that the means varied from 57 to 494 ml./min. on room air, and from 51 to 49 ml./min. on air supplied from a com-

3 OXYGEN AND INFANT RESPIRATION 285 pressed air cylinder (P > 1). Fig. 2 illustrates the results from this series of control observations. In some of these experiments the babies had been in the plethysmograph for less than 2 min. before the control period started, and we think it is likely that the decrease in respiration rate and increase in tidal air during compressed air administration is a reflexion of the fact that we had not obtained truly basal conditions. The method of statistical treatment will be discussed below Room air Air from 62 - cylinder E 6 - ' 58 _ 56 ~ 54_: > 52 e 5 S 48 ' c43 : E :29 17 E 16 15, 14 ~ Time in min Fig. 2. Graph 8howing the means of the scaled figures for the control period and the means of the scaled figures for the test period on compressed air. The vertical lines represent the 95% confidence limit of the means. After the baby had been receiving its air supply from a compressed air cylinder, the testing gas mixture was given. This gas, too, was passed through the Marriott's bottle and, using a mask with such a considerable volume as the one described (1.5 L), there was not an immediate change in the concentration of oxygen which the baby breathed. All our experiments were timed from the moment when the new mixture was applied. Serial sampling at 15 sec. intervals into evacuated sampling tubes showed that when 1% 2 was admitted the concentration of oxygen in the mask had reached about 45 % in 15 sec., and was very nearly 1% at the end of 1 min. This analysis was carried out in very few experiments, but the conditions were sufficiently standardized to presume similar results for all. An experiment would be regarded as ideal if an infant placed in the plethysmograph quickly settled down to apparent sleep. After the infant had been in the plethysmograph for 2 min. we hoped to obtain a period of 5 min. during which the infant slept with no movement of limbs or facial grimaces. At the end of this 5 min., the mask would be placed over the infant's face, with 19-2

4 286 K. W. CROSS AND PAMELA WARNER air from a compressed air cylinder already running into it at 5 I./min., and respirations during a further 5 min. of deep sleep would be recorded. At the end of this time the gas under test (1% 2, 6% 2 +4% N2, or 15 % 2+85% N2) would be turned on, and the baby was required to sleep for another period of 5 min. Finally, it was hoped to switch back to air from the compressed air cylinder while the baby was still in deep sleep without movement, so that the respirations should return to the control level Room air: 15% E 58 ;56- E54 ~52,o 5 ~48- z l C _17 E ~ Fig E 6 c Z 54 > 52 W o cl E a. -a -S r-room air:. 6% C2 - I E 6.E 58 E 56 m 54 > 52, 5 f c 43 E 39 ' 37 o 35 m E 29 _ : _ 17 E16?,o m Time in min..room air: 1% 2 I Time in min. Time in mn Fig. 3a. Fig. 3 b. Fig. 3c. Graphs showing the means of the scaled figures for the control period and the means of the scaled figures for the experimental period when the baby breathed (a) 15% 2, (b) 6% 2 and (c) 1% O.. The vertical lines represent the 95% confidence limit of the means. As these infants were not narcotized, it will be realized that such an ideal experiment was seldom possible, and it was obvious that steps had to be taken to reduce the time as much as possible. As soon as it was established that air from a compressed air cylinder caused no sigificant change in the minute volume of the infant, the first two control periods of the experiment were telescoped by placing the mask on, with the air running, at the end of the 4th min. after the infant had reached 'basal' levels, thus saving 5 min. In practice, also, the last 5 min. on air had to be abandoned, as we rarely obtained readings during it. The following criteria were finally set for the performance of a satisfactory experiment: (1) The infant must have been lying in the plethysmograph for 2 min. before recording was started. (2) The infant must have continued lying quite still for a further period of 5 min., during the last min. of which the mask, with compressed air flowing, would be placed over the face-this was the control period. (3) The infant must have continued to lie still while oxygen/nitrogen mixtures were passed through the mask. We aimed to do this for a further 5 min., but less than this was accepted if the

5 OXYGEN AND INFANT RESPIRATION 287 infant moved or cried before the time elapsed. As it is our experience that the minute volume rises frequently in the minute preceding movement or crying, the minute before such movements was rejected from our results. (4) If the infant sighed during a satisfactory record, so that the pen overran the edge of the recording paper, the minute in which this occurred was rejected, but the rest of the record was accepted if there were none of the contra-indications stated above. Selection of material. The subjects used in this study were normal infants in the nursery of St Mary's Hospital. There is no doubt that we have selected the more peaceful infants for this work, and it is possible that in making this selection we have unconsciously chosen babies who are at a different stage of reflex maturity from their more restless neighbouirs. At present we can see no method for determining the truth or falsity of such a speculation, but it should be noted that a baby that is restless on one day may be quite suitable for experiments on another. It will also be noted that the range of the minute volumes in the control periods tends to be lower than the range reported for normal resting babies in a previous communication (Cross, 1949). One was disinclined to persist in an experiment if the baby slept and vet showed a widely variable minute volume. It was felt that by applying the gas under test at a suitable moment one would to some extent be able to obtain results which fitted into preconceived ideas if these variable subjects were used. RESULTS In order to obtain the results presented here, 269 observations were made on 141 normal babies. From these we have been able to select 61 observations on 36 different babies which have fulfilled the criteria for a satisfactory experiment. With the great range of minute volumes which normal babies exhibit (up to 23% of the average of the control period in this series), it is obvious that a statistical analysis had to be made to determine whether the apparent changes following exposure to high or low oxygen tensions are part of the normal variation of the baby's respiratory pattern, or whether they are likely to represent a real response to the gas under test. To make this analysis of the results from different babies who have been subjected to the same experimental procedure, it was necessary to scale the figures obtained for minute volumes so that a baby who had a high minute volume would not weight the mean results. The method chosen was to take the arithmetic mean of the five minutes of the control period and use this mean as a factor for converting the figures of the control period so that they would average 5 ml. The same factor was applied to the figures obtained for the experimental period. These scaled figures were then used in the statistical analysis. An example will make this clear. With baby 1, Table 1, the arithmetic mean of the 5 min. of the control period is 764, and multiplying all through by the factor 5/764, we obtain 522, 51, 496, 469 and 52. During the period when 6 %h oxygen was being administered we obtain 422, 496, 576, 522 and 483. The figure of 5 ml. to which the results were scaled was chosen because it was approximately the same as the normal minute volume of the newborn babies (Cross, 1949). It is thought that this is a fair method of scaling the results, for it is found that there is a positive correlation between the arithmetic mean of

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7 OXYGEN AND INFANT RESPIRATION 289 the D min. of the control period and their range; thus, by scaling up and down to a mean of 5 ml. one tends to equalize the range. Fig. 4 shows part of eight tracings from seven babies who breathed a mixture with a high oxygen concentration at the beginning of the second minute shown. It will be seen that within 15 sec. of administering 1% oxygen the tidal air diminishes with no marked change in the respiratory rate. After one minute of oxygen administration the tidal air returns towards the original value and the respiratory rate begins to rise. This general pattern is repeated, in different -wa xi vi xi ii i iii. 5 S. 27. iv. 5 (I) iv. 5 (I) Fig. 4. Traces from 7 different babies, each showing the minute preceding and the 2 min. during the administration of 1 or 6% 2 in inspired air. The time dimension has been shortened pantographically before photographic reproduction. The numbers and dates to the right of each trace may be used to identify the subject in the Tables 1 and 2. The lowest two traces for one baby show a sigh in each control period, which is very common in the sleeping child. Traces: Upper, respiration, inspiration downwards; lower, automatic integrator (Cross, 1949). degrees, in the other cases illustrated, but it is by no means always so clear-cut. The lowest two traces, which are from the same baby, are interesting because on each occasion when the baby received oxygen the tidal air temporarily diminished, although in the upper of the two traces the first minute on oxygen showed an increase in minute volume compared with the average of the control period (43 ml./min. compared with an average of 46 ml./min.), while, in the

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10 292 K. W. CROSS AND PAMELA WARNER lower trace, there is a diminution of minute volume in the first minute on oxygen compared with the control period (4 ml./min. compared with 424 ml./min.). It should be further noted that the increase in the respiration rate may begin before the tidal air has returned to normal (e.g. baby 16, Table 2). Respiratory rates and tidal air volumes were corrected to standard figures of 33 respirations/min. and 15 ml. by a procedure similar to that adopted for minute ventilation volumes. The actual arithmetic means for the 61 observations are: Minute volume ml. Respiration rate 33.5/min Hence average tidal air 335 = ml. Tables 1, 2 and 3 show the results of experiments on 33 babies who breathed mixtures with high or low concentrations of oxygen. The actual minute volumes and respiration rates are recorded, but the arithmetic means and the standard deviations refer to the scaled figures. As the method of scaling used was one which depended on the mean of the control period, the standard error of the means of the control period are not given, for they have no independent variance. Significance was tested with 'Student's' t test, with t = (l-x2)/a2vn2 where l= mean of control period, Y2= mean of experimental minute under test, u2 = standard deviation between babies for that minute, and n2 = number of observations in that minute. In Figs. 2 and 3 (a)-(c), the arithmetic means for the scaled minute volumes, respiration rates and tidal airs are shown, and the 95% confidence limits for means obtained for the period of breathing the mixture are drawn in. It will be seen that the pattern of the response to high oxygen is very similar to what would be expected from a close inspection of Fig. 4. There is a statistically significant fall in the minute volume during the first minute of administration of high oxygen, which is achieved by a highly significant diminution of tidal air. After this the tidal air returns to the original value, but the respiration rate increases, so that the minute volume becomes significantly raised compared with the control period. There is a strikingly similar pattern in the responses to breathing 1 % 2 or 6 % 2. In the case of the responses of the babies to 15 %2, we find that there is at first a statistically significant increase in the minute volume, which is not well maintained. This increase in the minute volume seems to be a mixed effect both on the respiration rate and the tidal air, although our results here are not very clear-cut. DISCUSSION Howard & Bauer (195) have carried out a study similar to ours in ten infants, and record results which differ widely from our findings. They found 'an average decrease in respiratory minute volume of 1 % with the administration

11 OXYGEN AND INFANT RESPIRATION 293 of 12 % oxygen' and 'an average increase in respiratory minute volume of 3% with exposure to a concentration of oxygen, 42-74% in the respired mixture'. The difference between our findings and those of Howard & Bauer may well be explained by differences of technique. They were using a plethysmograph with a neck seal, the disadvantages of which have been discussed previously (Cross, 1949). Further, they only state the minute volume for certain selected minutes (less than one reading for each 4 min. of observation, and the basis of selection is not stated). There is no information about the respiration between readings, which appears to be very important in view of our finding that the infant responds to high oxygen in a diphasic fashion. Howard & Bauer draw attention to the marked differences between their findings and those of Dripps & mroe (1947), but it is felt that the lack of continuity of observation, and the less critical technique of the former, make this comparison inadmissible. In comparing our own results in babies with those of Dripps & mroe in adults, we find that the general pattern of the changes in minute volume to high and low oxygen concentration is very similar, but in the babies the results seem to be more clear-cut. Thus Dripps & mroe report that when adults breathe 1% 2 after room air the minute ventilation volume diminishes by 3-1 %. The probability of obtaining this result by chance was 1 in 15. In the babies who were treated comparably, the diminution of minute volume was 12 %, and the probability of this being a chance finding was less than 1 in 1. We have no figures exactly comparable with theirs for low oxygen in the inspired air, but while with their adults breathing 145 %2 there was an average increase of 5 1./min. (about 6-7 %) at the 6-8 min., our babies, breathing 15 % oxygen, showed an increase in minute volume of 6-3% for the average from to the 5th min., and the increase in the 1st and 2nd min. was highly significant. In making this comparison, therefore, either the baby is more sensitive in its response to oxygen-rich mixtures than the adult, or else the method which we have used detects this response more clearly than that of Dripps & mroe. Our results on babies seem to lie somewhere between those of Dripps & mroe on the adult human, and of Watt, Dumke & mroe (1943) on trained unanaesthetized dogs. By analogy with work on animals, we assume that the changes in minute volume to high and low oxygen are due to a diminished and increased drive respectively from the carotid body on the respiratory centre, but there seems to be no way of confirming this in the intact human subject. There is an interesting difference between the method by which the baby achieves a dimininished minute volume as an immediate response to high oxygen and the method employed by animals as described by von Euler & Liljestrand (1942). From Figs. 3 (b) and (c) it is quite clear that the baby makes this adjustment by decreasing the tidal air only, whereas von Euler & Liljestrand,

12 294 K. W. CROSS AND PAMELA WARNER working on chloralosed cats and dogs, state that there is an 'almost instantaneous, sometimes very considerable reduction in respiratory rate and amplitude' when 1% 2 was substituted for air, and Hejneman (1943) also found a decrease in respiratory rate as well as tidal air in rabbits anaesthetized with urethane. Thus, in these four species there is in all cases a diminution in tidal air in the 1st min. when high oxygen is given, but the baby appears to differ from the animals in not showing a diminution in respiration rate. We cannot exclude, of course, the possibility that this difference depends upon the animals receiving an anesthetic. After the initial fall in minute volume when the baby is receiving 6% or 1 / oxygen, there is an increase above the resting value, and this increase we refer to as a 'secondary rise'. This 'secondary rise' is recorded by Dripps & mroe, and also by Alveryd & Brody (1948), who studied the respiratory rate and expired minute volume 2 and 3 min. after the inhalation of 1% 2 in adult human subjects. They found an increase in minute volume of 154% (S.D. = 2793, P <.1). They state that the 'respiration frequency showed a certain, though insignificant increase during oxygen inhalation', but a study of their Table 1 shows that the mean tidal air of their five subjects rose from 437 to 45 ml. per breath (+2-9%), while the mean respiratory rate on 1% 2 rose from 11F8 to 13-2 respirations per minute (+11-9%). Their findings show, therefore, that 8 % of the increase in minute volume on high oxygen at 2-3 min. is due to increased respiration rate. In babies, we find that there is no average rise in tidal air in the 3rd-5th min. on 6% 2, but that the respiration rate is increased by about 9 %; therefore the pattern in the two cases seems to be not essentially dissimilar. The mechanism of this secondary rise in minute volume to high oxygen has been discussed by Dripps & mroe (1947), but in the case of the intact babies we can clearly have nothing to add to this discussion beyond remarking that the reflex producing diminution of tidal air and the reflex response causing increased respiration rate can operate at the same time, as is well shown in Fig. 4. It would seem that the response of the newborn baby to high and low oxygen suggests, by analogy with animal experiments, that the infant has an active carotid body reflex. The differences which are observed between the baby and adult animals may be attributed to species, age or anaesthetics, and there is at present insufficient information to be certain on these points. SUMMARY 1. The changes in respiratory minute volume, respiration rate and tidal air have been studied in a series of normal infants in response to high and low oxygen concentrations in inspired air. 2. As in the adult human subject, the immediate response to high oxygen

13 OXYGEN AND INFANT RESPIRATION 295 concentrations is that the minute volume diminishes. In babies, this is due only to a decrease of tidal air. After 1-2 min. the minute volume rises, because the tidal air has returned to normal and the respiration rate has increased. 3. With 15 %2 there is an increase in minute volume, which is apparently due to slight increases in both tidal air and respiration rates. 4. The comparable work on adult human subjects and adult animals is mentioned. The possible causes of the differences found are discussed, but in the absence of more detailed evidence on adult animals and man, no conclusions as to the causes of these differences can be reached. We wish to express our thanks to Professor A. St G. Huggett and Dr Reginald Lightwood, who have generously allowed us the facilities of their laboratories and wards, and who have helped us at all stages of the investigation; to the Medical Research uncil, who paid the expenses of our technician, Mr T. R. Nichol, who has given valuable and conscientious work; and to the British Oxygen mpany, who kindly made up the gas mixtures for this investigation and supplied them free of charge. We would like to thank Sister K. A. Taylor and her staff, who have cheerfully accepted our interruption of ward routine in the Maternity Department. Particuilar thanks are also due to Mr P. Armitage, of the Medical Research uncil Statistical Research Unit, who advised us on the statistical treatment which should be applied to our findings. REFERENCES Alveryd, A. & Brody, S. (1948). Acta physiol. Scand. 15, 14. Boyd, J. D. (195). Personal communication. Clark, G. A. (1935). J. Physiol. 83, 229. Cross, K. W. (1949). J. Physiol. 19, 459. Dripps, R. D. & mroe, J. H., Jr. (1947). Amer. J. Physiol. 149, 277. von Euler, U. S. & Liljestrand, G. (1942). Acta physiol. Scand. 4, 34. Hejneman, E. (1943). Acta physiol. Scand. 6, 333. Howard, P. J. & Bauer, A. R. (195). Amer. J. Dis. Child. 79, 611. Watt, J. G., Dumke, P. R. & mroe, J. H., Jr. (1943). Amer. J. Physiol. 138, 61.