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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
METHODS
Fifteen, normal, full-term infants were studied with the informed consent of their mothers, many
of whom assisted at the recording sessions. Three mothers received pethidine more than 6 h before
birth; one mother received pethidine within 2 h of birth while the others received no analgesia or
NO2 and 02 only. All were vaginal-vertex deliveries and none required resuscitation. Respiratory
recordings were made with the infants asleep, most commonly after a feed. Recordings lasted for
as long as possible: in one infant study only 6 min of recording was possible but in all the other
tests, recording lasted for 20 min or longer. In all infants, respiration was measured in terms of
the output of a 4-lead, transthoracic impedance pneumograph (Olsson & Victorin, 1970) and in
twelve infants, in addition, by means of a barometric plethysomograph based on the technique
described by Drorbough & Fenn (1955) and which has been shown to give accurate and consistent
results 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 the
electroencephalogram (e.e.g.) and electro-oculogram (e.o.g.) using bilateral electrodes and the
observation of eye movements (Anders, Emde & Parmalee, 1971).
In preliminary tests, a close correlation was demonstrated between the outputs of the impedance
pneumograph and that of a pneumotachograph, positioned in a face mask. This served to calibrate
the pneumograph tracing but in the same series of tests, the results of which have been published
elsewhere (Fleming, Levine & Goncalves, 1982), it was also shown that application of the face mask
significantly distorted the breathing pattern. These tests also showed that the pneumograph output
was affected by non-specific movements of the body but that these could be distinguished from
spontaneous sighs by recording tidal C02, sampled from the nose at a flow rate of 100 ml minand analysed with a Beckman LB2 infra-red analyzer. The outputs of e.e.g., e.o.g. and pneumograph
electrodes, the pressure transducer within the plethysmograph and the CO. analyzer were recorded
in parallel on a multi-channel recorder (Devices M19) while the respiratory signals were also
recorded on FM tape (Racal-Thermionic, Store-4 recorder).
section, there was considerable variation in the respiratory responses at various post-natal ages,
1-2
4
A
AnAAAAAftitRl
if/<A
. ArtrAAllt\4A MltAAAAr
,AA14AAA444AA4
Vi
L_
Insp.
_ _ _ _ I_
ir
F 1 _ ~~n
VO
dL
P2i Q
20 s
Fig. 1. Traces to show the sequence of processing. A, the computer plot of the output of
the impedance pneumogram (inspiration (insp.) downwards and in arbitrary units)
including a spontaneous sigh and apnoeic pause. B, an enlargement of the trace within
the rectangle in A with super-imposition of the output ofthe peak detection program where
the vertical line p is proportional to inspiratory tidal volume (VTi), q to inspiratory time
(Ti), r to expiratory tidal volume (VTe) and 8 to expiratory time (Te). C, is the output of
the peak detection program corresponding to the whole of trace A. D, E and F show
sequential values, corresponding to the breaths in A of the fractional difference of,
respectively, f, VT and PE from the mean on the ordinate against time on the abscissa.
Where
V = (VTi + VTe) f= T + TX and PE = VT Xf.
In F, the respiratory response has been fitted with a damped cosine curve. Traces A and
C-F inclusive are shown on the same time scale.
but there was also variation in the separate responses of VT andf. On some occasions, both VT and
f were initially depressed following the disturbance and then recovered monotonically to control
levels. On other occasions, VT responded with an oscillatory pattern whilef responded monotonically.
On yet other occasions, both VT andf responded with an oscillatory pattern. We judged that values
for PE, the minute volume of ventilation, was the simplest and most consistent estimate of
respiratory output and in the present study, respiratory responses have been analysed in terms
of this variable only.
The simplest type of system which responds to a transient disturbance in a similar way to the
monotonic and oscillatory respiratory patterns which we observed may be described by a second
order, differential equation:
d2y/dt2 + 2un gdy/dt + wn2y = F(t),
(1)
where y = (PE -fE)/ TE and where f is the damping factor and Wn is the natural frequency of
oscillation (radians s-1) (Burghes & Graham, 1980).
Here 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 two
constants C and Cn determine the characteristics of the system (Bayliss, 1966). We can classify the
types of response to a transient disturbance in terms of the value of C. If C < 0 then the response
takes the form of an increasing oscillation and the system is unstable. If 6 = 0 then the system is
undamped and will oscillate about the equilibrium state continuously with an angular frequency
Wn. If 0 < C < 1 then the system is underdamped and will oscillate with decreasing amplitude. If
C = 1 then the system is critically damped and will return to equilibrium in the shortest possible
time without oscillating. If C > 1 then the system is over-damped and will return asymptotically
to equilibrium, again without oscillating. We used two classes of solution of t (for t > 0): First, for
critical damping ( = 1),
(2)
y = yoe wnt (1 + Wn ),
here yo is the amplitude of the initial deviation.
Secondly for the underdamped response (C < 1),
y = Aef'wntcos[(nV(1 ) .t+q$],
(3)
here A is the amplitude of the oscillation obtained when there is no damping, i.e. for =00 and
9 has the form of a phase factor. yo, A,9 are constants whose values are dependent upon the precise
value of F(t) and since this is undefined by our measurements we cannot assign any significance
to them. The effect of F(t) is to determine the value of y and its derivative dy/dt at t = 0. We have
assumed that for the early responses which appeared to fit the critically damped case that the
derivative of y at time t = 0 is zero; which gives eqn. (2) in which there is one undetermined
constant. This assumption was not made for the underdamped case and so we have two
undetermined constants A and 0. The value of 0 can be estimated by inspection of the ventilation
(Fig. 7). At the start of the recovery after the sigh (i.e. at t = 0) y is negative and rising. The
argument of the cosine must be between 2fr and 3fr at t = 0, which means that 2fr < 0 < 3X7. It
is easy to show that the ratios of successive maxima are independent of A and q$ as are the intervals
between successive zero crossings.
Curve fitting procedure
Each 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 capable
of 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 was
superimposed on the original response curve and the parameters adjusted by trial and error until
an approximate match was obtained. The parameters were then refined by an iterative procedure
which 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 new
parameter which gave the largest fall in E was adopted and the procedure repeated. When none
of the shifted parameters gave a fall in E then the shifts themselves were halved one at a time to
find which new shift gave the largest fall in E. This new shift was adopted and the minimization
was continued in this way until the changes in E and the fitted parameters were small. This
procedure converged rapidly. Finally the fitted curve was plotted superimposed upon the data. In
order to compare the fit of responses of different magnitude, E/A max was calculated for each fitted
curve 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 the
series as a whole in Fig. 2. Recordings were made in all infants in the first 1-2 days:
Baby
number
4 _
R.
U l
*e
IIU.
12
13
19
20
21.
22
?'41
;-h
261
..
8*
2)'7/ l0
on
z71
2
34
Days
3844926
B 51 68 41
810
Age
12
14
16
18 20 2224 26
Weeks
28
33
18
28
11
12
13
36
25
33
12
12
12
17
30
Fig. 2. A summary of the ages of individual infants at which respiratory recordings were
made. Below: B the total number of spontaneous sighs recorded in non-r.e.m. sleep within
each age range indicated and A the corresponding number of response curves which could
be fitted.
0*9
0-8
0-7
C
.E
-C
0-6
0-5-
en
0*4
0-2
01
57-112
113-224
13-24 25-48 49-95 96-144 15-28 29-42
Hours
Days
Fig. 3. A graph to show the relation between the frequency of sighs recorded during
non-r.e.m. sleep and post-natal age. Each point represents the mean frequency of sighs
min-' + s.E. of mean.
in thirteen infants, three or more recordings were made and in nine, the period of
observation was 4 months or more. This Figure also summarizes the total number of
sighs 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
7
VENTILATOR Y RESPONSES TO SIGHS IN INFANTS
only in part due to the fact that more recordings were made in these infants. It was
also due to the fact, as is illustrated in Fig. 3, that the frequency of sighs diminished
with post-natal age so that from approximately 2 months onwards, only a very few
sighs occurred during a typical 20-30 min period of non-r.e.m. sleep. This paucity
was enhanced by another factor. In a proportion of older infants, respiration
recovered so rapidly to control levels following a sigh and apnoeic pause, that the
response could not be fitted satisfactorily. This point is discussed below. We also
observed that, as is illustrated in Fig. 6, with increasing post-natal age, frequency
of respiration diminished and, in general, that the frequency and depth of breathing
became much more regular.
2A
-2
-2
-2
-2
C~~~~~~~~~2
20 s
Fig. 4. Traces illustrating respiratory response curves which could not be satisfactorily
fitted with cosines. For description, see text. Each trace is presented as the fractional
difference of values of PE from the mean.
following a sigh that all that could be said was that the responses were very highly
damped. Three of these were in infants of less than 3 days of age: the remaining five
were in infants of 3 months or more and in these, fitting was made yet more difficult
because the relatively low frequency of respiration yielded very few points for fitting.
Lastly, in fifty-one cases, the respiratory responses to spontaneous sighs and apnoeic
pauses were so irregular, as is shown in Fig. 4C, or so slight as to be indistinguishable
from noise that fitting was either impossible or possible but only with a very large
error.
,. 222018 -AA
i 16 14 -AAAA
12 -
AAAAAAA
~~A A
CU
0
M
64- 6
A
0
Ar
&&AA
AA
OA
000
1000 U
aoooo
00 0
0ooo0o9ooooooooooooogo"
0-05
0-10
0-15
0-20
ol IONI 1m51a
l
0-25 0-30
E/A max
0-35
0-40
0-45
Eo 05 1
0-50
0-55
Fig. 5. The distribution of E/A max (see text). Open circles represent respiratory response
curves recorded from infants less than 48 h of age: open triangles, infants of more than
48 h of age.
Together, this group of seventy-one unfittable responses accounted for slightly less
than a quarter of the total number recorded but it was unevenly distributed. It
accounted 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 responses
could only be fitted with rather large errors. This is illustrated in Fig. 5 in which the
distribution of E/A max has been plotted. Out of a total of 250 fitted curves, sixteen
were fitted with an error of 31 % or more and of these, all but three occurred in infants
of less than 1 day old. If an error of 20 %, which might be regarded as more acceptable,
is taken, this accounted for 188 or 75 % of the curves and of the residual sixty-two
curves with a greater error, forty-four (71 %) were found in traces from infants of up
to 48 h. For the purposes of presentation of results in this paper, e.g. Fig. 8, only
the respiratory response curves fitted with an error of 20 % or less have been
considered but the trend observed with data derived from curves fitted with an error
of 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. Impedance
pneumograms before and following a sigh and apnoeic pause are shown at the ages
indicated. The same traces, processed and expressed as the fractional deviation of
P from the mean on the same time base, are shown in Fig. 7 A with the fitted response
9
VENTILATOR Y RESPONSES TO SIGHS IN INFANTS
curves superimposed. As is indicated from the values of E/A max in no case was the
fitted error greater than 15%. The values for the two constants, fi the damping
coefficient, (= - on), and T, the observed period of oscillation [= 2rr/wn v (1 - 2)]
are also given for each curve. These indicate that: at the earliest age, the response
is critically damped: at 47 h, a small overshoot appears with an oscillatory period
of 22-5 s and, with increasing post-natal age, the response becomes progressively
underdamped and the oscillatory period diminishes but, at a post-natal age of 5
months or so, the damping coefficient increases towards initial levels while T remains
unchanged or diminishes further.
+ Insp.
Age
23 h
20s
_AM4'A
VW 38 days
_Wvw
C _
47 h
94 days
VVYYV_206 days
F
Sigh
Fig. 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 sigh
and ensuing apnoeic pause. All are shown with the same time scale.
10
This trend with post-natal age was seen in all the infants in this series and the
changes 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 highly
damped, that the degree of damping diminished over the first 6 days and thereafter
increased. Linear regression of cos 0 upon age showed a highly significant negative
trend initially (d.f. 92, t = 8-98, P < 0-001) and a less significant positive trend from
Age Sigh(S)I
a
23 h
-010 T= Infinity
=3
012=(criticall
E
1
Is
amax
B Pole diagram
f
d
ly damped)
b 47 h
0-7
0*6
0-5
/2 _
fk I I
S max01=_As
0.4
Tr _ %% e, _
=zs
0-2
'
c 38 days
ES
0 -12-0
=-004
T=
14s
-0 15
Amax
2w
- a -0 0
-0. 1 0 -0-05
d 94 days
IS
Amax
=015
=-0.02
T=125s
e 151 days
Is
A9-0-094T=12p5s
0
=0-09
1.0s
01
Amax
f 206 days
=
0-10
j3-0-097 T
10-0 s
20 s
Fig. 7. A, the same traces as in Fig; 6, processed and presented in each case as the fractional
deviation of PE from the mean. Inset is the scale for ordinate and abscissa. Superimposed
on each response curve is the fitted cosine curve from which the values for the damping
factor, fi, and period of oscillation, T, given with each curve are derived together with
the error of fitting, E/A max. B, an S-plane Pole diagram in which values for fi and T
from the curves a-f in Fig. 7 A have been plotted on the axes -fl and 2v/T. An example
is given to show the derivation of On as the distance to a given point along a line from
the 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 the
averaged 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 scatter
of individual 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 varying
rates 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 by
the 68th day. In Baby 26, on the other hand, cos 0 fell from 0-62 to 0 37 between
0 80-719
29
0-6-
<,0.5-Ll
0
21
7
05425
T4
03-
>
02
12
10
co
~~~~~~~I
14
LO
ey
11
26
C4
~co
"IO
.
//, .CL
0),
v' ',
Days
Hours
0-8
031-
~~~~~~~~~~~~~~~~~~~~2
0-7-
0-1-
26
~~~~~~~~~
~~6
1
06
Q414'
19 29
0-2
0.1co b
IV
e o anv
of rli
Fig
CN fitte
2
of I~
pointrSummary
CV)
O
L~0
C')
by th
24and48 itthnfellmuchmore#lowlyreachn le - hn0N 1 C 9)
Days
Hours
20t de
Fig. 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 each
point, fitted with an error of 20 % or less within the age ranges indicated.
0
~.
24 and 48 h; it then fell much more slowly reaching less than 0-1 by the 94th day
and was still only 0-13 on the 206th day. The curves from the nine infants followed
for 4 months or more reached their nadir between the 26th and 111th days. The trend
thereafter was much more difficult to determine because, as described above, the
number of sighs in any given recording session in the older infants was relatively few.
DISCUSSION
The present series of experiments has involved a substantial processing chain from
raw respiratory data to the final presentation of respiratory stability in terms of
damping coefficient and oscillatory period and at each stage a number of qualifications
have to be applied which affect any conclusions which may be drawn. These are
considered in turn.
The respiratory data were obtained by non-disturbing therefore necessarily
indirect recording techniques, namely the impedance pneumograph and the barometric
plethysmograph. The most direct method, pneumotograph and face mask, introduces
changes in the pattern of breathing (Askanazi, Silverberg, Foster, Hyman, Milic-Emili
& Kinney, 1980; Fleming et al. 1982) and was used only to show that the indirect
methods were accurate. The processed data from the two outputs were virtually
identical. The disadvantages of the impedance pneumograph - its inability to
measure tidal volume quantitatively and its susceptibility to non-specific body
movements - were not found to be of any great importance since, for the purposes
of analysis, we were principally concerned with relative changes in TIE over short
periods while the use of the C02 analyser assisted in distinguishing between
respiratory and non-respiratory movements. We were therefore as certain as we could
be that the respiratory data which were subsequently processed were unaffected by
phase or other form of distortion.
This type of transient analysis could only be applied in non-r.e.m. sleep since
respiration 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 from
chemoreceptors 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 the
first few days after birth. This may simply be an index of the variability of breathing
pattern seen at this age, but not in the older infants, which has also been observed
by other workers (Hathorn, 1978; Waggener et al. 1982). The type of responses varied
considerably even in the same infant during the same recording session. It is possible
that a better description of the responses may have been achieved by the use of third
or even fourth order equations. We have not explored this possibility since our
approach in this, the first attempt to determine respiratory stability in infant or adult
in quantitative terms, has been to limit the number of constants. This possibility must
therefore remain open.
13
14
15
VENTILATOR Y RESPONSES TO SIGHS IN INFANTS
not necessarily be regarded as dangerous since the majority will be self-limiting. They
may well be overlooked by parents or paediatricians and they will be most likely to
occur during non-r.e.m. sleep when the extrinsic and intrinsic respiratory drives
associated 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 not
developed the mature type of response at 3-4 months of age since, at this time, the
time 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 age
that the greatest evidence of sudden death during sleep, in otherwise apparently
normal infants, occurs (Naeye, 1980). The possibility that such disasters might be
prevented by identifying infants who might be vulnerable, using the techniques
described in this paper, could provide an additional motive for an extended study
of respiratory stability in the new-born.
These studies were generously supported by grants from Action Research - The National Fund
for Research into Crippling Diseases (A/8/1114), and the National Institutes of Health (PHS HD
09457). We would like to acknowledge the help of Dr Sue Evans of Bristol University Computer
centre, Dr Andrew Smith, Department of Physiology, Bristol University, and Mrs Zona Wilson.
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