J. Physiol. (1984), 347, pp. 1-16 1With 8 text-figure8Printed in Great Britain

THE DEVELOPMENT OF STABILITY OF RESPIRATION IN HUMANINFANTS: CHANGES IN VENTILATORY RESPONSES TO

SPONTANEOUS SIGHS

BY PETER J. FLEMING, ARTHUR L. GONCALVES, MICHAEL R. LEVINEAND SUSAN WOOLLARD

From the Departments of Child Health and Physiology, Bristol University

(Received 14 December 1982)

SUMMARY

1. Serial respiratory recordings using impedance pneumography and barometricplethysmography were made from shortly after birth to 7 months in fifteen normalfull-term infants. Each recording was made with the infant asleep and sleep state wasestimated from records of electroencephalogram and electro-oculogram made inparallel.

2. The respiratory records obtained during non-rapid eye movement (r.e.m.) sleepwere analysed with computer assistance and stretches of the record, approximately1 min before and up to 2 min after a spontaneous sigh and ensuing apnoeic pause,were processed and presented as sequential values of the fractional deviation of '.the breath by breath minute volume, from the mean. That part ofthe sequence whichrepresented the respiratory response to the sigh was then fitted with second orderequations representing the critically or underdamped response. The results werepresented for each curve in terms of 6, the damping ratio and Wn, the frequency ofthe undamped respiratory oscillation.

3. Three-quarters of the responses could be so fitted with an error of 20% or less.The residual responses were mainly from infants within a few days of birth. In theyoungest infants (4 days or less), the respiratory response to a sigh was highly stablebut sluggish: during the period 4-8 days to 3-4 months, the oscillatory perioddiminished from ca. 25-12 s and respiration was potentially unstable since a smallreduction in the damping factor would cause prolonged oscillation while, from 3-4months, the more mature type of response which was stable with a rapid recoverysupervened.

4. The possible mechanisms responsible for this trend are discussed in terms of thefactors thought to determine respiratory stability in the adult together with thepossible relevance of the results to the normal process of respiratory adaptation atbirth and to the respiratory difficulties encountered by some infants in the new-bornperiod and early infancy.

INTRODUCTION

Shortly after birth, breathing becomes continuous and, after some hesitation,regular but there is some suggestion that full respiratory control is not achieved

1 PHY 347

P. J. FLEMING AND OTHERSuntil days or even weeks after birth. The mature respiratory response to hypoxiaconsisting of a sustained hyperpnoea is not seen until the end of the first week in thehuman infant (Brady & Ceruti, 1966) or until 6 weeks in the kitten (Schweiler, 1968).The sensitivity of the respiratory response to inhaled CO2 whether measured understeady-state conditions (Rigatto, Brady & Torre Verduzco, 1975; Krauss, Klain,Waldman & Auld, 1975; Frantz, Adler, Thach & Taeusch, 1976), or as the pressuregenerated by occlusion at end-expiration (Thach & Taeusch, 1976) is reported toincrease with post-natal age while it is only from about the 20th day after birth thatthe respiratory response to CO2 is more marked in non-rapid eye movement (r.e.m.)sleep than in r.e.m. sleep in the human infant (Davi, Sankaran, McCallum, Cates &Rigatto, 1979) and in the monkey (Guthrie, Standaert, Hodson & Woodrum, 1980)as it is reported to be in the adult (Phillipson, Murphy & Kozar, 1976). In addition,periodic respiration commonly occurs in a substantial proportion ofnormal, full-terminfants for up to 6 weeks or more (Hoppenbrouwers, Hodgeman, Harper, Hoffman,Sterman & McGinty, 1977).

This last observation raises the question as to how stable respiration actually isin the new-born period and whether in view of the changes in respiratory chemoreflexactivity, outlined above, there is a period of uncertainty in respiratory control. Sucha period of uncertainty would not be unexpected in a control system which had not,prior to birth, had to make accurate responses to chemical, thermal, metabolic andother stimuli while the interest of such a period, if it could be shown, would be thatit might explain the origin and nature of the respiratory difficulties encountered bya proportion of infants in the new-born period. This point has not yet been studiedsystematically. Hathorn (1978), using cross-correlation techniques, showed that themajority of infants in a small series in the first week after birth were able to maintainchanges in tidal volume and respiratory frequency exactly out of phase, anarrangement which should make for a stable respiratory output. But whether otherfactors thought to influence respiratory stability such as lung-to-receptor circulationtime, CO2 and 02 controller gain and tissue stores also operate in the new-born andwhether such factors alter with post-natal age, is not known.We have approached this question by analyzing the respiratory response to

spontaneous sighs and the ensuing apnoeic pause (Cross, 1954) in a group of normal,full-term infants serially from birth until 7 months of age and have estimatedrespiratory stability at each age in terms of the damping coefficient and oscillatoryperiod. This has shown a clear trend with post-natal age and the results are discussedin terms of the normal respiratory adaptation at birth and in deviations from thiswhich might affect respiratory control. A preliminary report of this work has beenpublished as an abstract (Fleming & Levine, 1982).

METHODS

Fifteen, normal, full-term infants were studied with the informed consent of their mothers, manyof whom assisted at the recording sessions. Three mothers received pethidine more than 6 h beforebirth; one mother received pethidine within 2 h of birth while the others received no analgesia orNO2 and 02 only. All were vaginal-vertex deliveries and none required resuscitation. Respiratoryrecordings were made with the infants asleep, most commonly after a feed. Recordings lasted foras long as possible: in one infant study only 6 min of recording was possible but in all the other

2

VENTILATOR Y RESPONSES TO SIGHS IN INFANTStests, recording lasted for 20 min or longer. In all infants, respiration was measured in terms ofthe output of a 4-lead, transthoracic impedance pneumograph (Olsson & Victorin, 1970) and intwelve infants, in addition, by means of a barometric plethysomograph based on the techniquedescribed by Drorbough & Fenn (1955) and which has been shown to give accurate and consistentresults for the measurement of tidal volume and respiratory frequency (Epstein, Epstein, Haddad& Mellins, 1980). The sleep state of the infants was estimated from parallel recordings of theelectroencephalogram (e.e.g.) and electro-oculogram (e.o.g.) using bilateral electrodes and theobservation of eye movements (Anders, Emde & Parmalee, 1971).

In preliminary tests, a close correlation was demonstrated between the outputs of the impedancepneumograph and that of a pneumotachograph, positioned in a face mask. This served to calibratethe pneumograph tracing but in the same series of tests, the results of which have been publishedelsewhere (Fleming, Levine & Goncalves, 1982), it was also shown that application of the face masksignificantly distorted the breathing pattern. These tests also showed that the pneumograph outputwas affected by non-specific movements of the body but that these could be distinguished fromspontaneous sighs by recording tidal C02, sampled from the nose at a flow rate of 100 ml min-and analysed with a Beckman LB2 infra-red analyzer. The outputs of e.e.g., e.o.g. and pneumographelectrodes, the pressure transducer within the plethysmograph and the CO. analyzer were recordedin parallel on a multi-channel recorder (Devices M19) while the respiratory signals were alsorecorded on FM tape (Racal-Thermionic, Store-4 recorder).Anoly8i8 of respiratory dataThe respiratory data were subsequently sampled at either 20 or 32 ms intervals usingADC (ARII)

of a PDP 11/10 laboratory computer, and the sampled signals stored on disc. These signals werefirst used to plot a respiratory trace on tracing paper which could be superimposed on the analogplot of the pneumograph or plethysmograph in each test so that (a) the sampling routine couldbe verified and, (b) from the parallel e.e.g. and e.o.g. signals, the periods of r.e.m. and non-r.e.m.sleep could be identified. Next, the sampled signals on disk were processed using a peak detectionprogram to yield sequential points ofmaximum voltage deviation corresponding to peak inspirationand expiration. In order to identify these points with certainty in the presence of artifacts suchas the heart beat, two parameters were used which could be varied at the time when the programwas run. These were: the minimum time and the minimum voltage change between end-inspirationand end-expiration or vice versa. Their value was determined from inspection of the respirationtrace plotted by computer and if they were correct, this meant that the program did not identifyas breaths any excursions in the recorded signal which were smaller than the window defined bythese values.The output of the peak detection program was also plotted on tracing paper as a bar chart as

is shown in Fig. 1. Each breath is represented by two vertical and two horizontal lines which areproportional to, respectively, inspiratory and expiratory volume (VTj, VTe) and duration (T1, Te).This bar chart was superimposed on the computer plot of the respiratory trace and if more thanone breath in 3 min was wrongly identified by the program, the value ofthe parameters was changedand the program re-run. A number of respiratory variables, such as the ratio of tidal volume toinspiratory duration, total breath duration and minute volume ofventilation, could be derived fromthese primary variables, which were stored on disk, but, in the present study, only sequential breathby breath values for tidal volume (VT), respiratory frequency (f) and their product, the breath bybreath minute volume of ventilation (PGE), were presented. Each of these variables was plotted onthe ordinate against time on the abscissa and, in order to facilitate comparison between the resultsin different tests, all values were expressed and plotted as the fractional differences from the meanof that study, (y-y)/y. This readily allowed the pattern of change of each variable after anydisturbance to be visualized, Fig. 1.For the purpose of the present study, only the respiratory responses to a spontaneous sigh and

the apnoeic pause which followed it were analysed. A sigh was defined as a breath which was atleast twice as large as the other breaths in the sequence and which -was followed by a transientfall in ventilation or an apnoeic pause which was itself twice as long as the average breath duration.Further, because of the irregularity of breathing in r.e.m. sleep, only the responses in non-r.e.m.sleep were analysed. Typically, as is shown in Fig. 1, a stretch of breathing recorded approximately1 min before and up to 2 min after each sigh was selected for analysis. As will be shown in the Resultssection, there was considerable variation in the respiratory responses at various post-natal ages,

1-2

3

4 P. J. FLEMING AND OTHERS

A l AnAAAAAftitRl if/

VENTILATORY RESPONSES TO SIGHS IN INFANTSHere F(t) is a function defining the imposed transient disturbance due to the sigh. Zero time is

measured from the start of recovery of the sigh. It is assumed that F(t) = 0 for t > 0. The twoconstants C and Cn determine the characteristics of the system (Bayliss, 1966). We can classify thetypes of response to a transient disturbance in terms of the value of C. If C < 0 then the responsetakes the form of an increasing oscillation and the system is unstable. If 6 = 0 then the system isundamped and will oscillate about the equilibrium state continuously with an angular frequencyWn. If 0 < C < 1 then the system is underdamped and will oscillate with decreasing amplitude. IfC = 1 then the system is critically damped and will return to equilibrium in the shortest possibletime without oscillating. If C > 1 then the system is over-damped and will return asymptoticallyto equilibrium, again without oscillating. We used two classes of solution of t (for t > 0): First, forcritical damping ( = 1),

y = yoe wnt (1+Wn ), (2)here yo is the amplitude of the initial deviation.

Secondly for the underdamped response (C < 1),y = Aef'wntcos[(nV(1 ) .t+q$], (3)

here A is the amplitude of the oscillation obtained when there is no damping, i.e. for 0=0 and9 has the form of a phase factor. yo, A,9 are constants whose values are dependent upon the precisevalue of F(t) and since this is undefined by our measurements we cannot assign any significanceto them. The effect of F(t) is to determine the value of y and its derivative dy/dt at t = 0. We haveassumed that for the early responses which appeared to fit the critically damped case that thederivative of y at time t = 0 is zero; which gives eqn. (2) in which there is one undeterminedconstant. This assumption was not made for the underdamped case and so we have twoundetermined constants A and 0. The value of 0 can be estimated by inspection of the ventilation(Fig. 7). At the start of the recovery after the sigh (i.e. at t = 0) y is negative and rising. Theargument of the cosine must be between 2fr and 3fr at t = 0, which means that 2fr < 0 < 3X7. Itis easy to show that the ratios of successive maxima are independent of A and q$ as are the intervalsbetween successive zero crossings.

Curve fitting procedureEach respiratory response to a sigh was first visually inspected and a decision made as to whether

it could or could not be fitted by either of the eqns. (2) or (3). If the curve was thought capableof being fitted, the appropriate equation was used and approximate values inserted: (yo, an for eqn.(2); A, fi, T, 0 for eqn. (3) where fi = -f and T = 2ff/conV 1 -i2). The calculated curve wassuperimposed on the original response curve and the parameters adjusted by trial and error untilan approximate match was obtained. The parameters were then refined by an iterative procedurewhich minimized the mean sum of squares of the differences between observed and calculated curve,E, where

E = N ob )In this procedure (Kowalik & Osborne, 1968) the parameters were altered by fixed amounts one

at a time. For each new parameter the alteration in the residual E was determined. That newparameter which gave the largest fall in E was adopted and the procedure repeated. When noneof the shifted parameters gave a fall in E then the shifts themselves were halved one at a time tofind which new shift gave the largest fall in E. This new shift was adopted and the minimizationwas continued in this way until the changes in E and the fitted parameters were small. Thisprocedure converged rapidly. Finally the fitted curve was plotted superimposed upon the data. Inorder to compare the fit of responses of different magnitude, E/A max was calculated for each fittedcurve where A max is the maximum displacement of y following a sigh.

RESULTS

The ages at which recordings were made in individual infants are shown for theseries as a whole in Fig. 2. Recordings were made in all infants in the first 1-2 days:

5

P. J. FLEMING AND OTHERSAge of babies at time of recording 0

1 2 34 2 4 6 810 12 14 16 18 20 2224 26 28 30Days Age Weeks

A 3844926 33 18 7 28 11 9 12 2 4 13B 51 68 41 36 25 7 33 12 12 12 2 5 17Fig. 2. A summary of the ages of individual infants at which respiratory recordings weremade. Below: B the total number of spontaneous sighs recorded in non-r.e.m. sleep withineach age range indicated and A the corresponding number of response curves which couldbe fitted.

0*9

C

.E

-C

en

0-8

0-7

0-6

0-5-

0*4 1

0-2

01 -

13-24 25-48 49-95 96-144 15-28 29-42 57-112 113-224Hours Days

Fig. 3. A graph to show the relation between the frequency of sighs recorded duringnon-r.e.m. sleep and post-natal age. Each point represents the mean frequency of sighsmin-' + s.E. of mean.

in thirteen infants, three or more recordings were made and in nine, the period ofobservation was 4 months or more. This Figure also summarizes the total number ofsighs recorded in non-r.e.m. sleep within the ranges of post-natal age indicated (B)together with the number of respiratory responses which could be satisfactorily fitted(A). It is clear that many more sighs were recorded in the younger infants. This was

6Babynumber

4 _R.

IIU. * *

1213192021.22 ..

261 . . * .2

U l *e

a

0 a

8 8

0 0 8 0

?'41 8* * *;-h * - -

/ l0 az71 - - _

)'7on

VENTILATOR Y RESPONSES TO SIGHS IN INFANTSonly in part due to the fact that more recordings were made in these infants. It wasalso due to the fact, as is illustrated in Fig. 3, that the frequency of sighs diminishedwith post-natal age so that from approximately 2 months onwards, only a very fewsighs occurred during a typical 20-30 min period of non-r.e.m. sleep. This paucitywas enhanced by another factor. In a proportion of older infants, respirationrecovered so rapidly to control levels following a sigh and apnoeic pause, that theresponse could not be fitted satisfactorily. This point is discussed below. We alsoobserved that, as is illustrated in Fig. 6, with increasing post-natal age, frequencyof respiration diminished and, in general, that the frequency and depth of breathingbecame much more regular.

2A

-2

-2

-2

2 C~~~~~~~~~2

-2 20 sFig. 4. Traces illustrating respiratory response curves which could not be satisfactorilyfitted with cosines. For description, see text. Each trace is presented as the fractionaldifference of values of PE from the mean.

For a number of reasons, a proportion ofrespiratory responses to spontaneous sighscould not be fitted with either eqn. (2) or (3). First, there were sighs or augmentedbreaths which were not followed by apnoeic pauses or periods of hypoventilation andwhichwere followed by no discernible respiratory response. Such transients, illustratedin Fig. 4A, were ignored and no attempt was made to fit them. Secondly, in twelvecases, a spontaneous sigh and ensuing apnoeic pause was followed by a second sighwith varying latency (Fig. 4B), the subsequent respiratory response was similarlyunfittable. Thirdly, in eight cases, respiration returned so rapidly to control levels

7

P. J. FLEMING AND OTHERS

following a sigh that all that could be said was that the responses were very highlydamped. Three of these were in infants of less than 3 days of age: the remaining fivewere in infants of 3 months or more and in these, fitting was made yet more difficultbecause the relatively low frequency of respiration yielded very few points for fitting.Lastly, in fifty-one cases, the respiratory responses to spontaneous sighs and apnoeicpauses were so irregular, as is shown in Fig. 4C, or so slight as to be indistinguishablefrom noise that fitting was either impossible or possible but only with a very largeerror.

,. 22-20-

c 18 -AAi 16 -

14-AAAA2 12 - AAAAAAA

CU ~~A A &&AA

0 6-M4-6 Ar0 AA A OAA _

000

E aoooo00 0 1000 Uz 0ooo0o9ooooooooooooogo" l olIONI 1m51a Eo 05 1

0-05 0-10 0-15 0-20 0-25 0-30 0-35 0-40 0-45 0-50 0-55E/A max

Fig. 5. The distribution ofE/A max (see text). Open circles represent respiratory responsecurves recorded from infants less than 48 h of age: open triangles, infants of more than48 h of age.

Together, this group of seventy-one unfittable responses accounted for slightly lessthan a quarter of the total number recorded but it was unevenly distributed. Itaccounted for one-third of the responses recorded in the first 8 days and for only 17%of the responses recorded thereafter.

In addition to those responses which could not be fitted, a number of responsescould only be fitted with rather large errors. This is illustrated in Fig. 5 in which thedistribution of E/A max has been plotted. Out of a total of 250 fitted curves, sixteenwere fitted with an error of 31 % or more and of these, all but three occurred in infantsof less than 1 day old. Ifan error of20 %, which might be regarded as more acceptable,is taken, this accounted for 188 or 75% of the curves and of the residual sixty-twocurves with a greater error, forty-four (71 %) were found in traces from infants of upto 48 h. For the purposes of presentation of results in this paper, e.g. Fig. 8, onlythe respiratory response curves fitted with an error of 20% or less have beenconsidered but the trend observed with data derived from curves fitted with an errorof 30% or less was found to be virtually identical.The pattern of responses to a sigh and apnoeic pause varied with post-natal age

and the sequence is illustrated by traces from one baby (26) in Fig. 6. Impedancepneumograms before and following a sigh and apnoeic pause are shown at the agesindicated. The same traces, processed and expressed as the fractional deviation ofP from the mean on the same time base, are shown in Fig. 7A with the fitted response

8

VENTILATORY RESPONSES TO SIGHS IN INFANTScurves superimposed. As is indicated from the values of E/A max in no case was thefitted error greater than 15%. The values for the two constants, fi the dampingcoefficient, (= - on), and T, the observed period of oscillation [= 2rr/wnv (1- 2)]are also given for each curve. These indicate that: at the earliest age, the responseis critically damped: at 47 h, a small overshoot appears with an oscillatory periodof 22-5 s and, with increasing post-natal age, the response becomes progressivelyunderdamped and the oscillatory period diminishes but, at a post-natal age of 5months or so, the damping coefficient increases towards initial levels while T remainsunchanged or diminishes further.

+ Insp. Age

A 23 h

20s

8 __AM4'A _ 47 h

C _ _Wvw VW 38 days

D / 94 days

E fVfV\ 151 days

F VVYYV_206 days

SighFig. 6. A series of traces, A-F, from one infant (no. 26) showing pneumograms (inspiration(insp.) downwards) obtained at the ages indicated. Each trace includes a spontaneous sighand ensuing apnoeic pause. All are shown with the same time scale.

The changes in respiratory stability with post-natal age can be compactlyrepresented in the form of an S-plane diagram with axes , and 2ff/T, equivalent topolar coordinates, Wn and 0. The values for , and T, derived from the curves a-f inFig. 7A have been so plotted in Fig. 7 B. Since it is known that stability dependsupon both the damping factor cos 0 and the undamped frequency of oscillation Wn,we may conclude that point a represents a highly stable but slow response; point ba stable but faster response: points c and d relatively unstable responses while pointse andfrepresent a more stable response with rapid recovery. This last type ofresponsemay be considered optimum and is consistent with the regular pattern of respirationseen in infants in this age range. By contrast, the points c and d indicate relativelyunstable respiratory control since a small increase in the value for f such that itbecame zero or positive would be associated with persistent respiratory oscillationwith maintained or increased amplitude.

9

10 P. J. FLEMING AND OTHERS

This trend with post-natal age was seen in all the infants in this series and thechanges in values for cos 0 and (On are summarized in Fig. 8A and B respectively.This confirms that the respiratory responses shortly after birth were relatively highlydamped, that the degree of damping diminished over the first 6 days and thereafterincreased. Linear regression of cos 0 upon age showed a highly significant negativetrend initially (d.f. 92, t = 8-98, P < 0-001) and a less significant positive trend from

A Curves fitted to pattern of ventilationAge Sigh(S)I after a sigh23 h

E=3012=-010

1 I amax (criticallT= Infinityly damped)

EAsS max01=_- =zs

E- - =-004 T= 14s0 -12-0S Amax -0 15

=015 =-0.02 T=125sIS Amax

E 0 A9-0-094T=12p5s=0-09

Is Amax

= 0-10 j3-0-097 T 10-0 s

B Pole diagramf 0-7

d 0*6e 0-5

0.4

' 0-2- a -0 0

-0.1 0 -0-05

1.0s01 1

20 s

Fig. 7. A, the same traces as in Fig; 6, processed and presented in each case as the fractionaldeviation of PE from the mean. Inset is the scale for ordinate and abscissa. Superimposedon each response curve is the fitted cosine curve from which the values for the dampingfactor, fi, and period of oscillation, T, given with each curve are derived together withthe error of fitting, E/A max. B, an S-plane Pole diagram in which values for fi and Tfrom the curves a-f in Fig. 7A have been plotted on the axes

-fl and 2v/T. An exampleis given to show the derivation of On as the distance to a given point along a line fromthe origin subtended by the angle 0.

the 15th day (d.f. 69, t = 1-99, P < 0 05). As is clear from the standard error of theaveraged values for cos 0 within each age range, there was considerable variation,most marked in the youngest and oldest infants. This was due not only to the scatterofindividual values but also the variation in the time course of trends with age. Thus,value for cos 0 in the first 24 h varied from I 0 to 0-28 and cos 0 declined at varyingrates over the subsequent days. For example, in Baby 21 cos 0 had fallen to low levels(< 0 1) by 96 h; it then remained low for the subsequent month and had risen bythe 68th day. In Baby 26, on the other hand, cos 0 fell from 0-62 to 0 37 between

a

b 47 h

c 38 days

d 94 days

e 151 days

f 206 days

2w

Is

/2 _ fk I I Tr _ %% e, _

VENTILATOR Y RESPONSES TO SIGHS IN INFANTSA

0 8-

0-7-19

0-6- 29

26 10 12 2 T

14 T

031- 60-1-

ey LO co C4~co +

V I ~~~~~~~I "IOv' ,' 0),//, ..CLHours Days

0-8

0-7- ~~~~~~~~~~~~~~~~~~~~29 4 1

06~~~~~~~~~~~626 1 ~ 1

3 Q414'19 29 2

0-2

0.1-

FigIVSummary of corli b e vpointr CN fitte o an 0 of 2i I~~. C . ~ ~C') L~0 O CV) -24and48 itthnfellmuchmore#lowlyreachn le hn0N 1 by thC9)

Hours Days20t deFig. 8. Summary of the relation between values for A, cos 6 and B, Wn and post-natal age.Each point represents the mean + s.E,. of the number of curves, given above eachpoint, fitted with an error of 20% or less within the age ranges indicated.

24 and 48 h; it then fell much more slowly reaching less than 0-1 by the 94th dayand was still only 0-13 on the 206th day. The curves from the nine infants followedfor 4 months or more reached their nadir between the 26th and 111th days. The trendthereafter was much more difficult to determine because, as described above, thenumber of sighs in any given recording session in the older infants was relatively few.

P. J. FLEMING AND OTHERS

Half of the curves showed no recovery from the lowest point: the other half showedsome recovery but in no case were the responses as highly damped as in the first daysafter birth. The changes in wO, as summarized in Fig. 8B, were more straightforward.Despite variation, wo in each infant showed a progressive rise with age: the positivetrend is significant (d.f. 172, t = 8-33, P < 0 001). Although the number of values issmall there is some suggestion above 2-3 months of age, that the frequency of theundamped respiratory oscillation becomes constant.

DISCUSSION

The present series ofexperiments has involved a substantial processing chain fromraw respiratory data to the final presentation of respiratory stability in terms ofdamping coefficient and oscillatory period and at each stage a number of qualificationshave to be applied which affect any conclusions which may be drawn. These areconsidered in turn.The respiratory data were obtained by non-disturbing therefore necessarily

indirect recording techniques, namely theimpedancepneumographandthe barometricplethysmograph. The most direct method, pneumotograph and face mask, introduceschanges in the pattern ofbreathing (Askanazi, Silverberg, Foster, Hyman, Milic-Emili& Kinney, 1980; Fleming et al. 1982) and was used only to show that the indirectmethods were accurate. The processed data from the two outputs were virtuallyidentical. The disadvantages of the impedance pneumograph - its inability tomeasure tidal volume quantitatively and its susceptibility to non-specific bodymovements - were not found to be of any great importance since, for the purposesof analysis, we were principally concerned with relative changes in TIE over shortperiods while the use of the C02 analyser assisted in distinguishing betweenrespiratory and non-respiratory movements. We were therefore as certain as we couldbe that the respiratory data which were subsequently processed were unaffected byphase or other form of distortion.

This type of transient analysis could only be applied in non-r.e.m. sleep sincerespiration in r.e.m. is highly irregular (but see Waggener, Frantz, Stark & Kronauer,1982). However, it is in non-r.e.m. that control is mediated principally by inputs fromchemoreceptors and the respiratory reflexes (Bryan & Bryan, 1978).As indicated above, difficulties were encountered in fitting a proportion of the

respiratory responses to spontaneous sighs. This was most obvious in infants in thefirst few days after birth. This may simply be an index of the variability of breathingpattern seen at this age, but not in the older infants, which has also been observedby other workers (Hathorn, 1978; Waggener et al. 1982). The type of responses variedconsiderably even in the same infant during the same recording session. It is possiblethat a better description of the responses may have been achieved by the use of thirdor even fourth order equations. We have not explored this possibility since ourapproach in this, the first attempt to determine respiratory stability in infant or adultin quantitative terms, has been to limit the number of constants. This possibility musttherefore remain open.

12

VENTILATOR Y RESPONSES TO SIGHS IN INFANTS

Po88ible physiological s8gniftcanceIt is worth emphasizing that three-quarters of the responses could be fitted with

relatively small error and this suggests that in these cases the respiratory controlsystem operates, as if it were under the control of a second order feed-back loop. Itis most probable that the dominant disturbing factor to which the system wasresponding was a chemical one associated with the sighs since the response lasted fortens of seconds rather than a breath or two which would have been expected if theresponse were a reflex one from, for example, lung receptors.We have assumed that the chemical disturbance consists of a rise in Pa (Biscoe

& Purves, 1967), a rise in pHa (Band, Cameron & Semple, 1969) and a fall in Pa&co,(Lewis, Ponte & Purves, 1980) associated with and starting 2-3 s after the sigh. Thisleads to a rapid fall in carotid body chemoreceptor afferent discharge which, togetherpossibly with the increased discharge from slowly adapting lung receptors, causes theperiod of apnoea during which time, the chemical changes in arterial blood arereversed to or even beyond control levels. The origin of the spontaneous sigh isuncertain. It has been proposed as representing the respiratory response to a fall inpulmonary compliance associated with alveolar collapse and mediated by receptorsin lung and chest wall (Bendixen, Smith & Mead, 1964). If so, this may explain therelative frequency of sighs in the immediate post-natal period before the functionalresidual capacity is established (Olsson & Victorin, 1970; Thach & Taeusch, 1976).Whatever the origin of the sigh, it has been found, in the present series, to providea consistent disturbance to respiration though clearly the variable depth of the sighand duration ofthe apnoeic pauses was likely to give rise to variable chemical changesin arterial blood.

It is possible that in the first few days of life, cardiovascular responses play a majorpart in the control of blood gases as in the fetus. This could explain the damped andvariable nature of the response to the sigh in the new-born.Evidence that the blood gas disturbances due to a sigh might be smeared by an

effective right to left shunt in the first few days of life is provided by Purves (1966a)in a study on new-born lambs. This could be due to the persistence of fetal vascularchannels. Such attenuation ofthe chemical changes in arterial blood may afford someprotection for the respiratory control system during the transitional periodimmediately after birth when it is being faced with, and having to respond to, stimulinever previously experienced.By the end of the first week or so, the respiratory responses are much less variable.

By this time, the damping ratio has fallen substantially below initial levels.Thereafter, it remains at low levels for some weeks and, in approximately half of theinfants studied, it then rose at about 3 months or more. Over the same period, theperiod of the undamped respiratory oscillation approximately halved.

It is possible that it is only an increasing influence and importance of the peripheralchemoreflex which could cause so marked a reduction in the period of the undampedrespiratory oscillation. Such an increase in the peripheral chemoreceptor effects mightarise from alterations in the signal seen by the receptor (e.g. from decreasing venousadmixture with increasing age), from increased sensitivity ofthe receptor or increasedcentral response to peripheral chemoreceptor inputs.

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P. J. FLEMING AND OTHERS

The contribution of the peripheral chemoreceptors to the dynamic respiratoryresponse to C02 has not been widely studied but it is clear from studies in theunanaesthetized adult dog (Dejours, 1963) and new-born lamb (Purves, 1966b) thatin the peripherally chemodenervated animal, the response has a longer latent periodand is substantially more sluggish. It would be of considerable interest to see whetherthe speed of the respiratory response to a standard CO2 stimulus does alter in thenew-born period and whether such alteration could be affected by peripheralchemodenervation.There is similar uncertainty about the factors which determine the degree of

respiratory damping. It has been proposed in the adult that important factors includethe relative importance oftissue stores ofC02 and 02, and C02 and 02 controller gainsand that, generally, C02 is the more important because its stores are greater andbecause the C02 gain is constant over a wide range (Cherniack & Longobardo, 1973).In support of such a view, these authors have pointed out that respiratory instabilityfollows a reduction in C02 stores, as following forced hyperventilation (Haldane &Priestly, 1905), at altitude (Fitzgerald, 1913) when, in addition, the effect of hypoxiastarts to dominate, or the experimental reduction in gain of the C02 controller in theadult (Cherniack, Euler, Homma& Kao, 1979) ornew-born (Wennergen& Wennergen,1980). Further, in both adult and new-born, respiratory instability may be reversedby giving, as appropriate, C02 or High 02 to inhale.

Despite these uncertainties, we think that two points of some importance emergefrom the present study. First, it would seem that the form of analysis of respiratorydata developed here may prove to be a valuable method of exploring quantitativelythe factors which contribute to respiratory stability, e.g. by selective, reversibleinterruption of known pathways in both adult and new-born animals. Secondly, thepresent results may shed some light on the origin of some respiratory difficultiesencountered by a proportion ofnew-born infants in the days or weeks following birth.Our results suggest that there is a period, after birth, which is longer than previouslythought, during which respiration is potentially unstable and, since only normal,full-term infants were studied, this must be considered as physiological. We havesuggested that this instability is concealed over the first week or so, by the unusualnature of the chemical disturbance: it becomes more obvious from the second weekonwards and it is only at a rather variable time after three months onwards that theadult type of stability, with rapid respiratory recovery from a disturbance, is evident.It remains entirely a matter of conjecture at present as to which of the factors,outlined above, is responsible for these changes. The sequence is, however, consistentwith the observations of Fenner, Schalk, Hoenicke, Wedenburg & Roehling (1973)and Hoppenbrouwers et at. (1977) that periodic respiration is not uncommon in aproportion of normal, full-term infants for some weeks after birth but rare in the first24 h.Our results have also shown considerable variation in the degree to which cos 0 is

reduced after birth and also the time course of this reduction. It may be supposedthat, due to biological variation, there are some infants in whom development of fullchemical control of breathing after birth is even less complete or is further delayedand in whom, in consequence, respiratory instability, as shown by episodes ofperiodicbreathing, would be yet more marked than in the present series. Such episodes need

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VENTILATOR Y RESPONSES TO SIGHS IN INFANTS

not necessarily be regarded as dangerous since the majority will be self-limiting. Theymay well be overlooked by parents or paediatricians and they will be most likely tooccur during non-r.e.m. sleep when the extrinsic and intrinsic respiratory drivesassociated with, respectively, the awake state and r.e.m. sleep are reduced or absent.This possibility would assume greater significance in those infants who have notdeveloped the mature type of response at 3-4 months of age since, at this time, thetime spent in non-r.e.m. sleep markedly increases (Parmalee, Wenner, Akiyama,Shultz & Stern, 1967). In this context, it may be of significance that it is at this agethat the greatest evidence of sudden death during sleep, in otherwise apparentlynormal infants, occurs (Naeye, 1980). The possibility that such disasters might beprevented by identifying infants who might be vulnerable, using the techniquesdescribed in this paper, could provide an additional motive for an extended studyof respiratory stability in the new-born.

These studies were generously supported by grants from Action Research - The National Fundfor Research into Crippling Diseases (A/8/1114), and the National Institutes of Health (PHS HD09457). We would like to acknowledge the help of Dr Sue Evans of Bristol University Computercentre, Dr Andrew Smith, Department of Physiology, Bristol University, and Mrs Zona Wilson.

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