- Email: [email protected]
Respiratory EMG findings in relation to periodic breathing in infants
Errr!,~ Humun Deuelopment, Elsevier
11 (1985) 43-60
43
EHD 00628
Respiratory EMG findings in relation to periodic breathing in infants M. J. O’Brien Depurtment
of Deoelopmental
Neurology, University of Groningen. Oostersrngel59. The Netherlunds Accepted
for publication
31 October
9713 EZ Groningen,
1984
Summary Intercostal and diaphragm EMG activity was analysed in periodically breathing infants. The aim was to investigate relationships between changes in tonic activity in the respiratory muscles and switches in spontaneous breathing pattern from periodic to continuous and vice versa. A heterogeneous group of 13 normal and neurologitally suspect infants was studied. They had all previously undergone polygraphic investigation and were selected because their polygraphic records showed at least three minutes uninterrupted periodic breathing (PB). PB appeared to represent an oscillation with a length of about 16 seconds superimposed on the basic state related irregular and regular breathing patterns. The development of a normal level of tonic activity in the respiratory muscles at the transition from state 2 to state 1 coincided with the switching from periodic to continuous breathing. Continuation of PB throughout a state 1 epoch in the presence of tonic respiratory muscle activity was exceptional. Sighs alone or sighs together with brief movements during state 1 were followed on occasion by a drop in tonic activity and a switch from continuous to periodic breathing. If the tonic activity rose again, PB either stopped or became less pronounced. TcPO, level measured in four infants rose when tonic activity rose and was lower during PB than during continuous breathing. The observations made in this study suggest that mechanical or chemical changes caused by changes in tonic activity level may affect the stability of respiratory control in infancy. periodic breathing; respiratory control;
respiratory state
EMG;
tonic activity;
polygraphy;
infant
breathing:
Introduction Periodic breathing (PB) is characterized by alternating respiratory pauses and short breathing episodes. It is common in preterm infants [2,3], in whom it decreases 0378-3782/85/$03.30
0 1985 Elsevier Science Publishers
B.V. (Biomedical
Division)
44
with maturation [21]. PB has a controversial significance as a risk factor for sudden infant death [8,14]. An oscillation in ventilation at the same frequency as PB has been demonstrated in non-periodically breathing infants during rapid eye movement (REM) sleep leading to the speculation that PB represents an extreme form of this oscillation [29]. Khoo et al. [15] have suggested that most ventilatory oscillations are controlled via the carotid chemoreceptors. They point out that even the slight reductions in oxygen saturation (SaO,) and rises in carbon dioxide partial pressure (PaCO,) which occur normally in sleep are enough to increase the gain in the respiratory control system sufficiently to cause it to oscillate in response to perturbations such as sighs. Since PB can be induced by hypoxia and abolished by hyperoxia or hypercapnia [1,27] and since transcutaneously measured PaO, (TcPO,) is lower during PB than during ‘regular’ breathing [17] it is reasonable to speculate, as Kalapesi et al. [13] have done that “spontaneous changes in respiratory pattern within the same sleep state may actually be chemically mediated”. One of the reasons why SaO, or PaO, falls in sleep is that changes in respiratory mechanics occur due to a reduction in intercostal muscle activity in active sleep [4,9,25].- This leads to increased chest distortion and reduction in thoracic gas volume and oxygen reserves [Ill. PB has been reported as occurring in both sleep states [6,7,12]. In the course of an earlier study we were intrigued to observe that a relationship seemed to exist between the level of tonic activity in the respiratory muscles in state 1 ( = quiet sleep) and the switching on and off of PB [25]. To pursue this observation respiratory EMG patterns during PB have therefore now been investigated in a heterogeneous group of infants having in common a pronounced tendency to breathe periodically. Despite large individual differences in amount of PB, relationships found between EMG changes and breathing pattern were consistent enough to suggest that sleep-state dependent alterations in neuromuscular function play an important role in switching on and off PB.
Subjects and Methods A periodic breathing bout is defined as a sequence of at least three central respiratory pauses of three seconds or more alternating with breathing bursts within about a one minute period. The polygraphic records of 153 infants, subjects in a variety of studies, were searched for uninterrupted bouts of periodic breathing lasting at least 3 min. This was done to ensure the selection of records with a chance of showing the type of relationship of interest between tonic EMG activity and PB. 13 records met this criterion. Relevant information concerning these infants is given in Table I. 11 infants had been investigated in our climatized polygraphic recording room. One of these had also been investigated in a normal clinical setting using portable equipment. Two infants were studied only in a clinical setting. Respiratory airflow was monitored in all infants via a nasal thermistor. Diaphragm EMG and ECG were recorded using surface electrodes placed subcostally in approximately the nipple line, right and left. Upper intercostal EMG was recorded in six infants via surface electrodes attached over an upper ribspace parasternally right and left.
Submental EMG and electro-oculogram (EOG) were measured in all 11 laboratory recordings and EEG (4 channels) in eight. All electrophysiological signals were measured using an institute-designed preamplification system based on the common average reference principle [20]. Transcutaneous blood oxygen tension (TcPO,) was monitored in four infants using a Hellige TcPO, monitor. Respiratory EMG signals were processed according to previously published techniques [20]. Briefly, the technique involves the gating out of the ECG component of the signal followed by subsequent rectification and moving window averaging. The artifact created by gating of the QRS complex is filled in via a feedback loop from the averager output. Thermistor and ECG signals were processed to yield respiratory and heart rates using a moving window event counting technique [28]. Signals measured were recorded on paper in all cases and during the 11 laboratory studies also on magnetic tape. In these 11 infants playbacks from tape of thermistor, averaged respiratory EMG and heart and respiratory rate signals were made off-line. Behavioural state profiles had been drawn up for each recording prior to the initiation of this study according to principles followed in this institute [24]. Briefly stated, eye condition (eyes open or closed), respiratory pattern (regular or irregular) presence and type of movements and presence or absence of crying are employed to
TABLE Infant No.
I Clinical
background
Duration of recording
Age (postterm)
Place studied
2 3
triplet - 2nd triplet - 3rd twin - 2nd; preterm.
6 days 7 days 3 days
laboratory laboratory laboratory
6 6 6
4 5
35 weeks gestation full term, normal preterm, 34 weeks gest.
5 days 6 wks
laboratory laboratory
6 6
6 7
exposed to high doses of diazepam in utero neurologically suspect perinatal asphyxia;
3 wks 5 wks
laboratory laboratory
S 5
8
congenital cytomegalovirus infection full term, normal
5 days 3 days
laboratory neonatal unit
10 days 5 days 8 days
laboratory laboratory laboratory
3.5 wks 6 days
infant ward neonatal unit
(h) 1
9B 10 11
intra-uterine growth retardation, postnatal cyanotic spells full term, normal agenesis of corpus
12 13
callosum; feeding difficulties perinatal asphyxia postnatal cyanotic
9A
spells
6 16.5 6 6 6
11 9.5
46
define five behavioural states. When breathing is periodic, a distinction is made between irregular and regular periodic breathing (abbreviated as IPB and RPB respectively) by focussing on the regularity of the oscillation and on the regularity of the breathing between the respiratory pauses. Data analysis The amount of time spent breathing periodically in each state was quantified per infant as percentage of the total time spent in that state. The duration of PB bouts was estimated also, the beginning of the first respiratory pause in a sequence being defined as the bout onset and the beginning of the first subsequent pause not followed by a discrete breathing burst as the end of the bout. Generalized body movements were not considered to interrupt a bout if PB continued immediately following the movement. The number of cycles and the average cycle length were estimated per bout. In order to quantitatively compare visually scored IPB and RPB patterns, ten consecutive cycles of each were selected from records showing both patterns. The thermistor signal was analysed to derive the following measurements: the length of respiratory pauses, the duration of breathing bursts, the number of breaths per burst, and the total duration of each breath (measured as the time from the beginning of one inspiration to the beginning of the next). Medians and interquartile ranges (I.Q. range) were calculated for each variable for IPB and RPB separately. The I.Q. range was taken as the measure of regularity in the data. The I.Q. ranges for each variable were compared across the two PB patterns using the Wilcoxon test. Polygraphic records and playbacks were visually scrutinized to define relationships between breathing pattern, EMG activity and, where available, TcPO, pattern.
Results Incidence of PB PB occurred almost exclusively in sleep. Table II gives the percentage of PB per state per infant. The incidence of PB in this heterogeneous group of infants was very variable. Three infants showed more PB in state 1 than state 2, in one the incidence was equal in the two states and the other nine showed more in state 2 than state 1. Characteristics of PB bouts Data on bout length, number of cycles per bout and average cycle length are presented for all the infants in Table Ill. The presence of a number of very long bouts results in highly skewed distributions for bout length and, correspondingly, number of cycles per bout in some infants. This reflects again the large individual variability in amount of PB. The figures for cycle length are more interesting since they do perhaps represent measurement of a fundamental process shared by all the infants. The average cycle length per bout varied within a narrow range in individual infants (the maximum interquartile range was 3 s), and varied somewhat more across the group (median values per infant varied from 13.4 to 20.1 s). The group median cycle length was about 16 s.
47 TABLE
II
Percentage
PB per state -
infant
state 1
state 2
state 3
2 3 4 5 6 7 8 9A 9B 10 11 12 13
13.1 0 3.4 2.1 44.0 27.0 17.1 20.8 0 0 20.6 58.7 14.5 38.0
39.8 23.7 19.4 29.0 52.8 x.3 17.1 56.8 30.5 28.2 9.1 25.8 18.2 45.0
22.3 6.9 0 0 0 0 0 0 0 0 0 0 0 0
Quantitative analysis of irregular and regular PB In Table IV raw data for each infant on pause and burst duration, number of breaths per burst, and total breath duration are presented for IPB and RPB separately. The interquartile range of all four parameters was greater during IPB than RPB (see Table V), confirming post-hoc the validity of the visual scoring of the two patterns. EMG features of PB EMG-indicated inspiratory efforts were always followed by airflow during both types of PB (see Fig. 1). There was thus no evidence that the periodic breathing was
thermistor
A
B
ri intercostal * diaphragm lb
Fig. 1. (A) irregular, (B) regular periodic breathing, both from infant no. 5. Intercostal and diaphragm EMGs are averaged (averaging window 100 ms) following gating of the QRS complex and full-wave rectification of the raw EMG.
* Average
2 3 4 5 6 7 8 9A B 10 11 12 13
1
Infant
56.75 53.5 53 56 96 42 134 54.15 134 85 72.5 85.5 90 12
P25
Bout length
cycle length was calculated
35 25 12 23 14 12 7 23 34 22 9 12 42 26
N (bouts)
(PSO), first and third quartiles
Medians
(s) *
III
TABLE
116.75 156.75 245 117.75 630 144.5 346 515.75 421 316 322 527 25-l 1034
80
60 103.25 192 61.75 534 102.5 212 461 293 231 249.5 441.5 167 962
IQ. range
of cycles
4 3 3.5 4 6 3 1.5 4 7 5 4 5 5 5
P25
Number
4 6 6 5 22.5 5.5 13 6 10.25 7 8 11 7 9.5
P50
7.75 9.25 14.5 12 41 9.5 24 36 21 17 15.5 21.5 13 66
P75
of cycles per bout
3.15 6.25 11 8 35 6.5 16.5 32 14 12 11.5 22.5 8 61
IQ. range
range (I.Q. range) for bout length (s). number
for each bout as bout length/no.
87 91 70 405 71 180 85 203.5 111.5 172 186 130 147
P75
P50
(P25, P75) and interquartile
14 13.3 14.4 12.5 15.0 12.1 13.7 14 19 17 17.9 16.8 15.8 15.3
P25
Average
16 15 15.7 13.5 15.4 13.4 14.6 14.7 20. I 17.5 19.2 18.2 16.6 16
P50
cycle length
17 16.7 16.5 14.9 16.0 13.8 15.2 15.3 21.6 18.6 20.1 18.7 11.4 16.7
P75
of cycles per bout, and Average
3 3.4 2.1 2.5 1 1.1 1.5 1.3 2.6 1.6 2.2 1.9 1.6 1.4
IQ. range
cycle length
IV
10 10 10 10 IO 9 10 10 10 10 10 10 10 10
P50
6.35 10 no RPB no RPB 6 6.0 10 9.9 10 6.0 10 5.8 10 7.8 no RPB 10 6.35 10 7.0 10 9.0 10 8.0 10 8.8
of PB cycles analysed. of breaths analysed.
5.5 4.8 4.6 5.55 6.4 4.0 5.6 5.3 7.3 5.6 6.9 6.0 9.0 6.8
2.2 4.0 1.9 2.6 3.4 1.4 3.8 0.9 2.5 2.1 1.8 1.8 2.5 3.0
N
I.Q. range
N *
J’S0
RPB
IPB
Pause length
* Number ** Number
1 2 3 4 5 6 7 8 9A B 10 11 12 13
Infant
1.1 2.4 1.6 2.0 2.5
0.4 0.6 0.6 1.6 1.2
1.7
8.55 11.6 10.5 6.45 8.8 8.4 7.0 7.6 13.8 10.95 10.45 9.8 6.3 8.8
P50
IPB
2.2 9.0 13.1 3.5 3.4 3.8 1.8 3.6 2.5 7.7 4.0 1.6 0.5 2.0
I.Q. range
Burst length
(PSO) and interquartile
I.Q. range
Quantitative data on IPB and RPB: Medians breath duration (s)
TABLE
11.35 no RPB no RPB 6.75 6.5 7.0 7.0 6.5 no RPB 8.85 11.1 10.1 10.0 8.8
P50
RPB
0.9 2.0 0.4 2.0 2.0
0.7 0.6 1.0 1.0 1.0
2.2
I.Q. range
1.Q. range 1 4 9 2 2 1.4 2 4 3 5 2 2 1 3
P50
7 8.5 10.5 3.5 6 5 5 7.5 8.5 10 5.5 7 5 5.5
IPB 1.Q. range
6.5 1 no RPB no RPB 4 0 4 1 4 1 6.5 1 5 1 no RPB 7 1 5 2 5 0 5 1 6 1
P.50
RPB
per burst
126 58 72
68 87 126 39 68 51 52 81
N **
IPB
1.2 1.2 0.9 1.6 1.4 1.8 1.4 1.1 not 1.3 1.8 1.3 not not
PSO
Total breath
for pause and burst length (s). number
No. of breaths
ranges (I.Q. ranges)
0.5 0.7 0.7
0.5 0.7 0.3 0.6 0.4 0.6 0.4 0.4
1.Q. range
duration
of breaths
P50
64 1.7 no RPB no RPB 23 1.8 41 1.6 44 1.6 66 1.1 45 1.4 measured 66 1.3 48 2.4 52 1.95 measured measured
N
RPB
0.2 0.6 0.5
0.5 0.325 0.3 0.3 0.3
0.1
1.0. range
per burst. and total
50
obstructive. During lengthy RPB bouts successive EMG bursts were similar, with the amplitude of successive inspiratory EMG peaks increasing and decreasing symmetrically during each burst. During IPB the EMG pattern of successive respiratory bursts was variable, and the within-burst sequencing of inspiratory peak EMG amplitudes was less predictable. Intercostal inspiratory activity was prominent during all RPB bursts, but was very variable in IPB bursts, being very low during some bursts, much more prominent during others. Tonic activity during the respiratory pause phase of the PB cycle was sometimes present in both intercostal and diaphragm EMG’s during RPB bouts. During IPB bouts tonic activity was absent during the pauses and the successive breathing bursts began and ended abruptly. (This subject is discussed in more detail below.) EMG findings related to the switching off or persistence of PB at the transition from state 2 to state 1 An IPB pattern was present leading up to the transition from state 2 to state 1 on 50 occasions. 44 of the transitions were characterized by a switch from IPB to the typical continuous regular breathing of state 1 (Type I transitions); six were characterized by a switch from IPB to RPB (Type II transitions). In the case of Type I transitions, tonic activity always built up in the diaphragm EMG signal (and, where recorded, in the intercostal signal also) coincident with the damping out of the respiratory oscillation. On the contrary, in three of the six Type II transitions (where PB continued) there was a conspicuous absence of diaphragmatic tonic activity throughout what was by all available criteria a state 1 epoch. Type I transitions are illustrated in Figs. 2, 3, 4A, 5B and 6B, Type II transitions are present in Figs. 5A, 6A and 6C. The switch in breathing pattern in Type I transitions was sometimes abrupt, sometimes more gradual. In the gradual transitions the apneic periods became progressively shorter and the breathing bursts longer until eventually a continuous regular pattern was established. As this happened the amplitude of the respiratory EMG oscillations progressively reduced and there was a build up of tonic activity, the level of which stabilized as the breathing pattern became continuous and regular. General movements often preceded or interrupted the above transition in respiratory pattern. In such circumstances tonic activity was higher after the phasic event than
TABLE Statistical and RPB
V analysis
(Wilcoxon
test) comparing
interquartile
ranges
of respiratory
parameters
Parameter
I.Q. range
P value
Length of pause Length of burst No. of breaths per burst Total breath duration
IPB > RPB IPB > RPB
0.02 -C P -C 0.05 P = 0.02
IPB > RPB IPB > RPB
P = 0.01 P < 0.01
during
IPB
51
thermistor
r180
cardiotach
150 it
T
intercostal
diaphragm
T
I
log
10
1OZc Fig. 2. Switch from periodic to continuous regular breathing in association with build up in tonic EMG activity in intercostal and diaphragm. The tonic activity is visible as an elevation in the baseline of the rectified averaged EMG. A logarithmic averager is used to accentuate the tonic activity changes. infant 9B. thermistor
diaphragm
U!M cog
bh-++++Pw-
,-
eeg r.f-c
I--J,-
ISOO/JV @w
r.c-p
#$&l%!#~wI Lf-c @wm iv ‘~_WWflY~~ ..II(
. T._l_T
w$~Yqvjw+j%Y-
_~,~_r~~~_~
~(.
I
71 --T I1’~-Tml”
Fig. 3. 27 min of polygraphic recording (infant 9B) to show cessation of PB as tonic activity builds up at the beginning of state 1. Transition point from state 2 to state 1 is indicated by a, from state 1 to state 2 by b. Oscillation in breathing rate during PB is clear in respiratory rate signal (moving window counter technique, window = 7.5 s). Note presence of tonic activity throughout the state 1 epoch. In this and subsequent compressed records individual breaths cannot be visualized. PB breathing bursts are clearly visible.
52
before and remained elevated during the ensuing epoch of continuous regular breathing. A TcPO, measurement was available for analysis in the case of 20 Type I transitions. A representative example of the TcPO, pattern associated with a typical transition is illustrated in Fig. 4A. In general, TcPO, levels oscillated slightly when breathing was periodic. As PB damped out and tonic activity developed, the TcPO, rose progressively. The onset of the TcPO, rise usually lagged the first indication of tonic activity by about ten seconds, a delay attributable in part to the response time
diaphragy
impedance
Fig. 4. Changes in TcPO, related to breathing pattern changes. In (A) TcPO, falls during IPB, oscillating slightly. It rises as tonic activity in the diaphragm develops and the breathing pattern becomes continuous. This infant, 9A, was recorded in a neonatal intensive care environment. The impedance respiration signal comes from a standard monitor (Hewlett-Packard). In (B) IPB resumes after a general movement early in state 2. TcPO, is slightly lower during PB. State transition points indicated as in Fig. 3.
53
of the PO, measurement system. TcPO, often minutes even after tonic activity had stabilized.
continued
to increase
Switching between continuous and periodic breathing within state I If regular continuous breathing had been established, switching
heart
to PB only
rate
B thermistor
heart
for several
i
a
rate
180
I
150
-1
log10
~4llNlH~l ~TTWTT-~~~
I -7 rr-r
-T--I
min
Fig. 5. (A) 33 min of polygraphic record (infant 5) showmg unmterrupted PB throughout a complete 1 epoch. Transition points as in Fig. 3. Tonic activity develops 6 min into the state in the intercostal minimal in the diaphragm. (B) Another state 1 epoch in the same infant (no. 5) showing switching PB at the state 2 to 1 transition as tonic activity reaches its maximum level. At the transition to state resumes as tonic activity falls. Transition points as in Fig. 3.
state but is off of 2 PB
54
occurred following phasic events. This occurred on 36 occasions in this material. Such switches always followed sighs associated often with startles, and less often with longer general movements. Tonic EMG activity sometimes dropped after the phasic event, a phenomenon not attributable to a change in posture. 18 of these bouts of PB (50%) involved seven or fewer cycles. One such bout is shown in Fig. 7. The EMG and thermistor signals during these short bouts revealed that the apneic periodic pattern faded gradually into an amplitude-modulated non-apneic pattern and finally into a non-oscillating regular pattern again. During this sequence, the
Fig. 6. Three 35-min samples of polygraphic recording from infant 11. (A) PB continues throughout a complete state 1 epoch, except for 3.5 min at the beginning of the state. despite the development of tonic activity in the diaphragm. Intercostal activity is artefactually low because the infant lay in a lateral position with the upper arm flexed across the chest, a posture which is associated with unsatisfactory intercostal EMG recording. Periodic heart rate oscillations are marked. (B) Tonic EMG activity in this state 7 , 4;h is normal and breathing is continuous throughout the state. IPB begins early in state 2. Posture supine. (C) PB throughout a state 1 epoch despite tonic activity in the diaphragm. Intercostal activity artefactually low, as in A. Heart rate oscillations during PB prominent. Note; this infant had an absent corpus callosum and had evidence of dissociated states, such as in Figs. 6B and C the development of tonic activity in the diaphragm 6 min before the state 2 to 1 transition. The EEG was also abnormal (not shown).
55
level of tonic activity rose and stabilized again. Although not illustrated, TcPO, levels were often slightly higher immediately after the sigh triggering these bouts of PB. Thereafter the TcPO, fell gradually during the early cycles in the bout, oscillating slightly. As tonic activity began to build up again and the PB pattern damped out, TcPO, rose again. The other 18 bouts of this type were longer, the number of cycles varying from 10 to 58. The longest bouts all spanned the transition from state 1 to state 2. The two most instructive examples are illustrated in Fig. 8. In the state 1 illustrated in Fig. 8A the eventual return to continuous breathing coincided with reestablishment of a high level of tonic activity. On the other hand, in the instance shown in Fig. 8B tonic activity was higher at one point during RPB than during the preceding regular continuous breathing. Respiratory pauses were shorter and there were more breaths per burst when tonic activity was high than when it was low or absent. At the very end of state 1, tonic activity normally disappears before the breathing pattern changes from regular to irregular. There was no consistent relationship between the timing of the disappearance of tonic activity and an eventual resumption of PB. There was likewise no consistent relationship evident between TcPO, levels and breathing rhythm changes at this time in the four infants in whom TcPO, was measured.
thermistor
intercostal
10 set Fig. 7. A sigh in state 1 followed but rises again as the respiratory
by a bout of PB. Note that tonic activity oscillation damps out. Infant 7.
in the diaphragm
falls initially
lb
56 A
thermistor
,
11,
,r,,r.‘,,,““.“-‘.
r,..
,‘..’
1 ....“.
1
.
I
I
,
E
120 150
1 60 30 0
intercostal
7
71
log 10
..
I
log10
I
I
I
I
II
I
II
11
”
”
”
”
”
min
thermistor
heart rate
150 120 60
resp. rate
30
E 0
I
log10
log10 I Fig. 8. (A) Infant 1. 21 min extract from a polygraphic recording showing switching from continuous to periodic breathing following a sigh in state 1. Tonic activity is slightly lower after the sigh in the diaphragm EMG and shows a falling trend. A later sigh plus general movement is followed by a further drop in tonic activity which then builds up again in association with restoration of a continuous breathing pattern. PB starts again following the next sigh and remains evident as tonic activity decays at the state 1 to 2 transition. (B) Infant 5. A similar compressed polygraphic record as in A. PB is triggered by a sigh and continues through the state 1 to 2 transition. Tonic activity levels in intercostal and diaphragm show both related and independent fluctuations. PB breathing bursts are longer and pauses shorter when tonic activity is high.
57
Discussion In this group of neonates, the oldest of whom was six weeks post-term, most PB bouts were short although occasional infants breathed periodically for up to an hour at a time. Despite the heterogeneity of the group, which precludes among other things any study of developmental aspects of PB, it is interesting that the average cycle length of 16 s is the same as the oscillation in non-apneic breathing found by Waggener et al. [29]. It seems worthwhile drawing attention again to the fact, previously pointed out [23,25], that the pattern of PB may be irregular or regular. That an experienced observer can as reliably distinguish between irregular and regular patterns of periodic breathing as between irregular and regular non-periodic continuous breathing is substantiated by the statistical differences listed in Table V. It seems that PB must be viewed as reflecting the expression of a respiratory system oscillation superimposed on the basic modulation in breathing rhythm associated with the two sleep states. In infants breathing non-periodically (or continuously) in sleep, two main differences in respiratory muscle EMG activity have previously been described between irregular breathing in state 2 and regular breathing in state 1 [19,25,26]. In state 2 sustained tonic activity is absent in both intercostal and diaphragm EMGs. Intercostal inspiratory activity is generally low but variable. Tonic activity builds up at the onset of state 1 in both intercostal and diaphragm EMGs. (Whether the pan-expiratory ‘tonic’ component in the diaphragm signal really originates from the diaphragm is open to question. Arguments for and against a true diaphragmatic origin have been advanced [10,18,20]. This will not be gone into further here since the exact source of the measured ‘tonic’ activity is not crucial to the significance of the observed relationships found in this study.) Intercostal inspiratory peak activity is higher and more consistent in state 1 than in state 2, while diaphragmatic inspiratory peak activity is correspondingly lower in state 1 than state 2. In the group of infants reported here, the EMG features during IPB were essentially as described above for irregular continuous breathing in state 2 except that the oscillation in respiratory amplitude was added. Tonic EMG activity was less consistently present during sustained RPB than during regular continuous breathing. The fact that PB can remain regular throughout what is clearly a state 1 epoch despite an absence of tonic activity, means that the regularity of the pattern per se cannot be the result of mechanical or chemical changes secondary to increased tonic activity. This lends support to the concept that central neural mechanisms and not peripheral reflexes are responsible for the patterning of (periodic) breathing in sleep into irregular and regular types. Animal experiments strongly suggest this, since elimination of all peripheral afferent information in dogs does not abolish the irregularity of breathing in REM sleep [22]. In these infants there was a consistent relationship between the development of tonic activity in the respiratory muscles at the transition from state 2 to state 1 and damping out of existing PB. This occurrence is reflected in the lower incidence of PB in state 1 than in state 2 in nine of the 13 infants. In the course of state 1, PB bouts interrupting continuous breathing were triggered by sighs or sighs plus generalized
58
movements, usually startles. Fleming et al. [5] have used the respiratory response to sighs as a way to estimate respiratory stability, measuring the damping coefficient and oscillatory period of the response. In the present study short PB bouts of this type were usually characterized by a transient drop in tonic EMG level. Damping out of the respiratory oscillation was typically accompanied by a renewed rise in tonic activity level and in TcPO,. The fact that the apparent link between tonic respiratory muscle activity and the switching off of periodic breathing is strongest at the beginning of state 1 and more variable later in the state suggests a change in sensitivity of control mechanisms in the course of state 1. That other unidentified factors must play a role in switching PB on and off can be concluded from the fact that on three occasions (involving two infants) PB persisted throughout state 1 despite an apparently normal build up of tonic diaphragmatic activity. A possible hypothesis to explain the observed relationship between tonic EMG changes and switching off of PB is that an increase in tonic respiratory muscle activity stabilizes the respiratory pump, thereby increasing thoracic gas volume and oxygen stores and leading to a reduction in tidal alveolar gas oscillations. The end result is a decrease in gain in the peripheral chemoreceptor control loop with consequent damping out of respiratory oscillations. Our observations that TcPO, rises as tonic activity builds up and respiratory oscillations damp out is consistent with this theory. So also are the observations of Lopes et al. [16] on the importance of diaphragmatic tonic activity in maintaining lung volume in premature newborns. Experimental administration of oxygen abolishes periodic breathing in preterm infants, although high concentrations may be required [3,17]. Perhaps what we observe is similar, the stability of the respiratory control system responding to normally occurring changes in blood gas tensions caused by spontaneous changes in neuromuscular activity. In this regard the relative paucity of TcPO, measurements and lack of PCO, measurements in this study limits further speculation along these lines. This study suggests that control of tonic activity in the respiratory muscles is a key factor governing the stability of the respiratory system in state 1, at least in early infancy. The neural mechanisms governing the level and pattern of tonic activity in state 1 need to be elucidated. The possibility that excessive amounts of PB in state 1 may reflect a defect in mechanisms controlling muscle tone in sleep deserves further investigation. Refined non-invasive EMG techniques such as those applied in the present study are valuable in this type of research. Acknowledgements The author is grateful to MS Y. Lems for carrying out the statistical analyses and preparing illustrations. The constructive help of Professor H.F.R. Prechtl is gratefully acknowledged. L.A. van Eykern developed the technical facilities which made this work possible. This research is supported by grant no. 13-51-91 from the Foundation for Medical Research Fungo, which is subsidized by the Netherlands Organization for the Advancement of Pure Research (ZWO).
59
References
1 Brady, J.P., Ariagno, R.L., Watts, J.C., Goldman, S.L. and Dumpit, F.M. (1978): Apnea. and aborted sudden infant death syndrome. Pediatrics. 62, 686-691. 2 Chernick. V., Heldrick, F. and Avery, M.E. (1964): Periodic breathing of premature Pediatr.. 64, 330-340.
hypoxemia infants.
J.
3 Fenner, A., Schalk. U.. Hoenicke, H., Wendenburg. A. and Roehling. T. (1973): Periodic breathing in premature and neonatal babies: incidence, breathing pattern, respiratory gas tensions, response to changes in the composition of ambient air. Pediat. Res.. 7. 174-183. 4 Finkel, M.L. (1975): Activity of respiratory muscles in newborn infants during wakening and sleep. J. Evol. B&hem. Physiol.. 1. 92-95. 5 Fleming, P.J., Goncalves, A.L., Levine, M.R. and Woollard. S. (1984): The development of stabihty of respiration in human infants: Changes in ventilatory responses to spontaneous sighs. J. Physiol.. 347. l-16. 6 Flores-Guevara, R., Plouin, P., Curzi-Dascalova, L., Radvanyi, M.-F., Guidasci, S.. Pajot. N. and Monod. N. (1982): Sleep apneas in normal neonates and infants during the first 3 months of life. Neuropediatrics suppl, 13. 21-28. 7 Guilleminault, C., Ariagno, R., Korobkin, R., Nagel, L., Baldwin, R., Coons, S. and Owen, M. (1979): Mixed and obstructive sleep apnea and near-miss for sudden infant death syndrome: 2. Comparison of near miss and normal control infants by age. Pediatrics, 64, 882-891. 8 Haddad, G.G. and Mellins, R.B. (1983): Cardiorespiratory aspects of Sids: An overview. In: Sudden Infant Death Syndrome, pp. 357-374. Editors: Tildon, J.T., Roeder, L.M. and Steinschneider, A. Academic Press, Inc., London-New York. 9 Hagan, R., Bryan. A.C.. Bryan, M.H. and Gulston. G. (1976): The effect of sleep state on intercostal muscle activity and rib-cage motion. Physiologist 19. 214. 10 Harding, R., Henderson-Smart. D.J., Johnson, P. and McClelland. M.E. (1979): Posturally related tonic activity recorded from the peripheral diaphragm in awake and sleeping lambs. J. Physiol. 292, 57p. 11 Henderson-Smart, D.J. and Read, D.J.C. (1979): Reduced lung volume during behavioural active sleep in the newborn. J. Appl. Physiol., 46, 1081-1085. 12 Hoppenbrouwers, T., Hodgman, J.E., Harper, R.M., Hofmann, E., Sterman, M.B. and McGinty. D.J. (1977): Polygraphic studies of normal infants during the first six months of life: III. Incidence of apnea and periodic breathing. Pediat.. 60, 418-425. 13 Kalapesi. Z., Durand, M.. Leahy, F.N., Cates, D.B., MacCallum, M. and Rigatto, H. (1981): Effect of periodic or regular respiratory pattern on the ventilatory response to low inhaled CO2 in preterm infants during sleep. Am. Rev. Respir. Dis., 123, 8811. 14 Kelly, D.H. and Shannon, D.C. (1979): Periodic breathing in infants with near-miss sudden infant death syndrome. Pediatrics, 63, 355-360. 15 Khoo. M.C.K., Kronauer, R.E.. Strohl, K.P. and Slutsky, A.S. (1982): Factors inducing periodic breathing in humans: a general model. J. Appl. Physiol. Respir. Environ, Exercise Physiol.. 53. 644659. 16 Lopes, J., Muller, N.L., Bryan, M.H. and Bryan, A.C. (1981): Importance of inspiratory muscle tone in maintenance of FRC in the newborn. J. Appl. Physiol., 51, 830-834. 17 Monin, P., Vert, P., Andre, M. and Vibert, M. (1979): Transcutaneous PO2 monitoring (TcP02) in the newborn during apneic spells, convulsions, cardiac catheterizations and exchange transfusions. In: Continuous Transcutaneous Blood Gas Monitoring. Birth Defects: original article series, Vol XV. no. 4, pp. 469-491. Editors: A. Huch. R. Huck and J.F. Lucey. Alan P. Liss, Inc., New York. 18 Muller, N., Volgyesi, G., Becker, L.. Bryan, M.H. and Bryan. A.C. (1979): Diaphragmatic muscle tone. J. Appl. Physiol.: Respir. Environ. Exercise Physiol. 47, 279-284. 19 O’Brien, M.J., Van Eykern, L.A. and Prechtl, H.F.R. (1980): Diaphragmatic intercostal and abdominal muscle tonic EMG activity in normal and hypotonic newborns. In: Ontogenesis of the brain, Vol. 3. Proceedings of the International Symposium Neuroontogeneticum Tertium, Charles University, Prague.
471-479.
60 20 O’Brien, M.J., Van Eykern. L.A. and Prechtl, H.F.R. (1983): Monitoring respiratory activity in infants - a non-intrusive diaphragmatic EMG technique. In: Non-invasive Physiological Measurements, Vol. 2, pp. 131-177. Editor: P. Rolfe. Academic Press, London. 21 Parmelee, A.H., Stern, E. and Harris, M.A. (1972): Maturation of respiration in prematures and young infants. Neuropadiatrie, 3, 294-304. 22 Phillipson, E.A. (1978): State of the art: Control of breathing during sleep. Am. Rev. Respir. Dis.. 118, 909-937. 23 Prechtl, H.F.R. (1972): Apparative oberwachung physiologischer Parameter post-partum. In: Perinatale Medizin, Band II, pp. 216-224. Editors: E. Saling and F.J. Schulte. Georg Thieme Verlag. Stuttgart. 24 Prechtl, H.F.R. (1974): The behavioural states of the newborn infant (a review). Duivenvoorde Lecture. Brain Res., 76, 185-212. 25 Prechtl, H.F.R., Van Eykern, L.A. and O’Brien, M.J. (1977): Respiratory muscle EMG in newborns: a non-intrusive method. Early Hum. Dev., 1, 265-283. 26 Prechtl, H.F.R., O’Brien, M.J. and van Eykern, L.A. (1979): Neonatal breathing in different states of sleep and wakefulness. In: Central Nervous Control Mechanisms in Breathing, pp. 443-455. Editors: C. von Euler and H. Lagercrantz. Pergamon Press, Oxford. 27 Rigatto, H. and Brady, J.P. (1972): Periodic breathing in preterm infants. I. Evidence for hypoventilation possibly due to central respiratory depression. Pediatrics, 50, 202-218. 28 Scholten, C.A. and Vos, J.E. (1982): Comparative investigation of the mathematical properties of some descriptors for biological point processes: examples from the human newborn. Med. Biol. Eng. Comput., 20, 89-93. 29 Waggener, T.B., Frantz III, I.D., Stark, A.R. and Kronauer, R.E. (1982): Oscillatory breathing patterns leading to apneic spells in infants. J. Appl. Physiol. Respir. Environ. Exercise Physiol., 52, 1288-1295.
11 (1985) 43-60
43
EHD 00628
Respiratory EMG findings in relation to periodic breathing in infants M. J. O’Brien Depurtment
of Deoelopmental
Neurology, University of Groningen. Oostersrngel59. The Netherlunds Accepted
for publication
31 October
9713 EZ Groningen,
1984
Summary Intercostal and diaphragm EMG activity was analysed in periodically breathing infants. The aim was to investigate relationships between changes in tonic activity in the respiratory muscles and switches in spontaneous breathing pattern from periodic to continuous and vice versa. A heterogeneous group of 13 normal and neurologitally suspect infants was studied. They had all previously undergone polygraphic investigation and were selected because their polygraphic records showed at least three minutes uninterrupted periodic breathing (PB). PB appeared to represent an oscillation with a length of about 16 seconds superimposed on the basic state related irregular and regular breathing patterns. The development of a normal level of tonic activity in the respiratory muscles at the transition from state 2 to state 1 coincided with the switching from periodic to continuous breathing. Continuation of PB throughout a state 1 epoch in the presence of tonic respiratory muscle activity was exceptional. Sighs alone or sighs together with brief movements during state 1 were followed on occasion by a drop in tonic activity and a switch from continuous to periodic breathing. If the tonic activity rose again, PB either stopped or became less pronounced. TcPO, level measured in four infants rose when tonic activity rose and was lower during PB than during continuous breathing. The observations made in this study suggest that mechanical or chemical changes caused by changes in tonic activity level may affect the stability of respiratory control in infancy. periodic breathing; respiratory control;
respiratory state
EMG;
tonic activity;
polygraphy;
infant
breathing:
Introduction Periodic breathing (PB) is characterized by alternating respiratory pauses and short breathing episodes. It is common in preterm infants [2,3], in whom it decreases 0378-3782/85/$03.30
0 1985 Elsevier Science Publishers
B.V. (Biomedical
Division)
44
with maturation [21]. PB has a controversial significance as a risk factor for sudden infant death [8,14]. An oscillation in ventilation at the same frequency as PB has been demonstrated in non-periodically breathing infants during rapid eye movement (REM) sleep leading to the speculation that PB represents an extreme form of this oscillation [29]. Khoo et al. [15] have suggested that most ventilatory oscillations are controlled via the carotid chemoreceptors. They point out that even the slight reductions in oxygen saturation (SaO,) and rises in carbon dioxide partial pressure (PaCO,) which occur normally in sleep are enough to increase the gain in the respiratory control system sufficiently to cause it to oscillate in response to perturbations such as sighs. Since PB can be induced by hypoxia and abolished by hyperoxia or hypercapnia [1,27] and since transcutaneously measured PaO, (TcPO,) is lower during PB than during ‘regular’ breathing [17] it is reasonable to speculate, as Kalapesi et al. [13] have done that “spontaneous changes in respiratory pattern within the same sleep state may actually be chemically mediated”. One of the reasons why SaO, or PaO, falls in sleep is that changes in respiratory mechanics occur due to a reduction in intercostal muscle activity in active sleep [4,9,25].- This leads to increased chest distortion and reduction in thoracic gas volume and oxygen reserves [Ill. PB has been reported as occurring in both sleep states [6,7,12]. In the course of an earlier study we were intrigued to observe that a relationship seemed to exist between the level of tonic activity in the respiratory muscles in state 1 ( = quiet sleep) and the switching on and off of PB [25]. To pursue this observation respiratory EMG patterns during PB have therefore now been investigated in a heterogeneous group of infants having in common a pronounced tendency to breathe periodically. Despite large individual differences in amount of PB, relationships found between EMG changes and breathing pattern were consistent enough to suggest that sleep-state dependent alterations in neuromuscular function play an important role in switching on and off PB.
Subjects and Methods A periodic breathing bout is defined as a sequence of at least three central respiratory pauses of three seconds or more alternating with breathing bursts within about a one minute period. The polygraphic records of 153 infants, subjects in a variety of studies, were searched for uninterrupted bouts of periodic breathing lasting at least 3 min. This was done to ensure the selection of records with a chance of showing the type of relationship of interest between tonic EMG activity and PB. 13 records met this criterion. Relevant information concerning these infants is given in Table I. 11 infants had been investigated in our climatized polygraphic recording room. One of these had also been investigated in a normal clinical setting using portable equipment. Two infants were studied only in a clinical setting. Respiratory airflow was monitored in all infants via a nasal thermistor. Diaphragm EMG and ECG were recorded using surface electrodes placed subcostally in approximately the nipple line, right and left. Upper intercostal EMG was recorded in six infants via surface electrodes attached over an upper ribspace parasternally right and left.
Submental EMG and electro-oculogram (EOG) were measured in all 11 laboratory recordings and EEG (4 channels) in eight. All electrophysiological signals were measured using an institute-designed preamplification system based on the common average reference principle [20]. Transcutaneous blood oxygen tension (TcPO,) was monitored in four infants using a Hellige TcPO, monitor. Respiratory EMG signals were processed according to previously published techniques [20]. Briefly, the technique involves the gating out of the ECG component of the signal followed by subsequent rectification and moving window averaging. The artifact created by gating of the QRS complex is filled in via a feedback loop from the averager output. Thermistor and ECG signals were processed to yield respiratory and heart rates using a moving window event counting technique [28]. Signals measured were recorded on paper in all cases and during the 11 laboratory studies also on magnetic tape. In these 11 infants playbacks from tape of thermistor, averaged respiratory EMG and heart and respiratory rate signals were made off-line. Behavioural state profiles had been drawn up for each recording prior to the initiation of this study according to principles followed in this institute [24]. Briefly stated, eye condition (eyes open or closed), respiratory pattern (regular or irregular) presence and type of movements and presence or absence of crying are employed to
TABLE Infant No.
I Clinical
background
Duration of recording
Age (postterm)
Place studied
2 3
triplet - 2nd triplet - 3rd twin - 2nd; preterm.
6 days 7 days 3 days
laboratory laboratory laboratory
6 6 6
4 5
35 weeks gestation full term, normal preterm, 34 weeks gest.
5 days 6 wks
laboratory laboratory
6 6
6 7
exposed to high doses of diazepam in utero neurologically suspect perinatal asphyxia;
3 wks 5 wks
laboratory laboratory
S 5
8
congenital cytomegalovirus infection full term, normal
5 days 3 days
laboratory neonatal unit
10 days 5 days 8 days
laboratory laboratory laboratory
3.5 wks 6 days
infant ward neonatal unit
(h) 1
9B 10 11
intra-uterine growth retardation, postnatal cyanotic spells full term, normal agenesis of corpus
12 13
callosum; feeding difficulties perinatal asphyxia postnatal cyanotic
9A
spells
6 16.5 6 6 6
11 9.5
46
define five behavioural states. When breathing is periodic, a distinction is made between irregular and regular periodic breathing (abbreviated as IPB and RPB respectively) by focussing on the regularity of the oscillation and on the regularity of the breathing between the respiratory pauses. Data analysis The amount of time spent breathing periodically in each state was quantified per infant as percentage of the total time spent in that state. The duration of PB bouts was estimated also, the beginning of the first respiratory pause in a sequence being defined as the bout onset and the beginning of the first subsequent pause not followed by a discrete breathing burst as the end of the bout. Generalized body movements were not considered to interrupt a bout if PB continued immediately following the movement. The number of cycles and the average cycle length were estimated per bout. In order to quantitatively compare visually scored IPB and RPB patterns, ten consecutive cycles of each were selected from records showing both patterns. The thermistor signal was analysed to derive the following measurements: the length of respiratory pauses, the duration of breathing bursts, the number of breaths per burst, and the total duration of each breath (measured as the time from the beginning of one inspiration to the beginning of the next). Medians and interquartile ranges (I.Q. range) were calculated for each variable for IPB and RPB separately. The I.Q. range was taken as the measure of regularity in the data. The I.Q. ranges for each variable were compared across the two PB patterns using the Wilcoxon test. Polygraphic records and playbacks were visually scrutinized to define relationships between breathing pattern, EMG activity and, where available, TcPO, pattern.
Results Incidence of PB PB occurred almost exclusively in sleep. Table II gives the percentage of PB per state per infant. The incidence of PB in this heterogeneous group of infants was very variable. Three infants showed more PB in state 1 than state 2, in one the incidence was equal in the two states and the other nine showed more in state 2 than state 1. Characteristics of PB bouts Data on bout length, number of cycles per bout and average cycle length are presented for all the infants in Table Ill. The presence of a number of very long bouts results in highly skewed distributions for bout length and, correspondingly, number of cycles per bout in some infants. This reflects again the large individual variability in amount of PB. The figures for cycle length are more interesting since they do perhaps represent measurement of a fundamental process shared by all the infants. The average cycle length per bout varied within a narrow range in individual infants (the maximum interquartile range was 3 s), and varied somewhat more across the group (median values per infant varied from 13.4 to 20.1 s). The group median cycle length was about 16 s.
47 TABLE
II
Percentage
PB per state -
infant
state 1
state 2
state 3
2 3 4 5 6 7 8 9A 9B 10 11 12 13
13.1 0 3.4 2.1 44.0 27.0 17.1 20.8 0 0 20.6 58.7 14.5 38.0
39.8 23.7 19.4 29.0 52.8 x.3 17.1 56.8 30.5 28.2 9.1 25.8 18.2 45.0
22.3 6.9 0 0 0 0 0 0 0 0 0 0 0 0
Quantitative analysis of irregular and regular PB In Table IV raw data for each infant on pause and burst duration, number of breaths per burst, and total breath duration are presented for IPB and RPB separately. The interquartile range of all four parameters was greater during IPB than RPB (see Table V), confirming post-hoc the validity of the visual scoring of the two patterns. EMG features of PB EMG-indicated inspiratory efforts were always followed by airflow during both types of PB (see Fig. 1). There was thus no evidence that the periodic breathing was
thermistor
A
B
ri intercostal * diaphragm lb
Fig. 1. (A) irregular, (B) regular periodic breathing, both from infant no. 5. Intercostal and diaphragm EMGs are averaged (averaging window 100 ms) following gating of the QRS complex and full-wave rectification of the raw EMG.
* Average
2 3 4 5 6 7 8 9A B 10 11 12 13
1
Infant
56.75 53.5 53 56 96 42 134 54.15 134 85 72.5 85.5 90 12
P25
Bout length
cycle length was calculated
35 25 12 23 14 12 7 23 34 22 9 12 42 26
N (bouts)
(PSO), first and third quartiles
Medians
(s) *
III
TABLE
116.75 156.75 245 117.75 630 144.5 346 515.75 421 316 322 527 25-l 1034
80
60 103.25 192 61.75 534 102.5 212 461 293 231 249.5 441.5 167 962
IQ. range
of cycles
4 3 3.5 4 6 3 1.5 4 7 5 4 5 5 5
P25
Number
4 6 6 5 22.5 5.5 13 6 10.25 7 8 11 7 9.5
P50
7.75 9.25 14.5 12 41 9.5 24 36 21 17 15.5 21.5 13 66
P75
of cycles per bout
3.15 6.25 11 8 35 6.5 16.5 32 14 12 11.5 22.5 8 61
IQ. range
range (I.Q. range) for bout length (s). number
for each bout as bout length/no.
87 91 70 405 71 180 85 203.5 111.5 172 186 130 147
P75
P50
(P25, P75) and interquartile
14 13.3 14.4 12.5 15.0 12.1 13.7 14 19 17 17.9 16.8 15.8 15.3
P25
Average
16 15 15.7 13.5 15.4 13.4 14.6 14.7 20. I 17.5 19.2 18.2 16.6 16
P50
cycle length
17 16.7 16.5 14.9 16.0 13.8 15.2 15.3 21.6 18.6 20.1 18.7 11.4 16.7
P75
of cycles per bout, and Average
3 3.4 2.1 2.5 1 1.1 1.5 1.3 2.6 1.6 2.2 1.9 1.6 1.4
IQ. range
cycle length
IV
10 10 10 10 IO 9 10 10 10 10 10 10 10 10
P50
6.35 10 no RPB no RPB 6 6.0 10 9.9 10 6.0 10 5.8 10 7.8 no RPB 10 6.35 10 7.0 10 9.0 10 8.0 10 8.8
of PB cycles analysed. of breaths analysed.
5.5 4.8 4.6 5.55 6.4 4.0 5.6 5.3 7.3 5.6 6.9 6.0 9.0 6.8
2.2 4.0 1.9 2.6 3.4 1.4 3.8 0.9 2.5 2.1 1.8 1.8 2.5 3.0
N
I.Q. range
N *
J’S0
RPB
IPB
Pause length
* Number ** Number
1 2 3 4 5 6 7 8 9A B 10 11 12 13
Infant
1.1 2.4 1.6 2.0 2.5
0.4 0.6 0.6 1.6 1.2
1.7
8.55 11.6 10.5 6.45 8.8 8.4 7.0 7.6 13.8 10.95 10.45 9.8 6.3 8.8
P50
IPB
2.2 9.0 13.1 3.5 3.4 3.8 1.8 3.6 2.5 7.7 4.0 1.6 0.5 2.0
I.Q. range
Burst length
(PSO) and interquartile
I.Q. range
Quantitative data on IPB and RPB: Medians breath duration (s)
TABLE
11.35 no RPB no RPB 6.75 6.5 7.0 7.0 6.5 no RPB 8.85 11.1 10.1 10.0 8.8
P50
RPB
0.9 2.0 0.4 2.0 2.0
0.7 0.6 1.0 1.0 1.0
2.2
I.Q. range
1.Q. range 1 4 9 2 2 1.4 2 4 3 5 2 2 1 3
P50
7 8.5 10.5 3.5 6 5 5 7.5 8.5 10 5.5 7 5 5.5
IPB 1.Q. range
6.5 1 no RPB no RPB 4 0 4 1 4 1 6.5 1 5 1 no RPB 7 1 5 2 5 0 5 1 6 1
P.50
RPB
per burst
126 58 72
68 87 126 39 68 51 52 81
N **
IPB
1.2 1.2 0.9 1.6 1.4 1.8 1.4 1.1 not 1.3 1.8 1.3 not not
PSO
Total breath
for pause and burst length (s). number
No. of breaths
ranges (I.Q. ranges)
0.5 0.7 0.7
0.5 0.7 0.3 0.6 0.4 0.6 0.4 0.4
1.Q. range
duration
of breaths
P50
64 1.7 no RPB no RPB 23 1.8 41 1.6 44 1.6 66 1.1 45 1.4 measured 66 1.3 48 2.4 52 1.95 measured measured
N
RPB
0.2 0.6 0.5
0.5 0.325 0.3 0.3 0.3
0.1
1.0. range
per burst. and total
50
obstructive. During lengthy RPB bouts successive EMG bursts were similar, with the amplitude of successive inspiratory EMG peaks increasing and decreasing symmetrically during each burst. During IPB the EMG pattern of successive respiratory bursts was variable, and the within-burst sequencing of inspiratory peak EMG amplitudes was less predictable. Intercostal inspiratory activity was prominent during all RPB bursts, but was very variable in IPB bursts, being very low during some bursts, much more prominent during others. Tonic activity during the respiratory pause phase of the PB cycle was sometimes present in both intercostal and diaphragm EMG’s during RPB bouts. During IPB bouts tonic activity was absent during the pauses and the successive breathing bursts began and ended abruptly. (This subject is discussed in more detail below.) EMG findings related to the switching off or persistence of PB at the transition from state 2 to state 1 An IPB pattern was present leading up to the transition from state 2 to state 1 on 50 occasions. 44 of the transitions were characterized by a switch from IPB to the typical continuous regular breathing of state 1 (Type I transitions); six were characterized by a switch from IPB to RPB (Type II transitions). In the case of Type I transitions, tonic activity always built up in the diaphragm EMG signal (and, where recorded, in the intercostal signal also) coincident with the damping out of the respiratory oscillation. On the contrary, in three of the six Type II transitions (where PB continued) there was a conspicuous absence of diaphragmatic tonic activity throughout what was by all available criteria a state 1 epoch. Type I transitions are illustrated in Figs. 2, 3, 4A, 5B and 6B, Type II transitions are present in Figs. 5A, 6A and 6C. The switch in breathing pattern in Type I transitions was sometimes abrupt, sometimes more gradual. In the gradual transitions the apneic periods became progressively shorter and the breathing bursts longer until eventually a continuous regular pattern was established. As this happened the amplitude of the respiratory EMG oscillations progressively reduced and there was a build up of tonic activity, the level of which stabilized as the breathing pattern became continuous and regular. General movements often preceded or interrupted the above transition in respiratory pattern. In such circumstances tonic activity was higher after the phasic event than
TABLE Statistical and RPB
V analysis
(Wilcoxon
test) comparing
interquartile
ranges
of respiratory
parameters
Parameter
I.Q. range
P value
Length of pause Length of burst No. of breaths per burst Total breath duration
IPB > RPB IPB > RPB
0.02 -C P -C 0.05 P = 0.02
IPB > RPB IPB > RPB
P = 0.01 P < 0.01
during
IPB
51
thermistor
r180
cardiotach
150 it
T
intercostal
diaphragm
T
I
log
10
1OZc Fig. 2. Switch from periodic to continuous regular breathing in association with build up in tonic EMG activity in intercostal and diaphragm. The tonic activity is visible as an elevation in the baseline of the rectified averaged EMG. A logarithmic averager is used to accentuate the tonic activity changes. infant 9B. thermistor
diaphragm
U!M cog
bh-++++Pw-
,-
eeg r.f-c
I--J,-
ISOO/JV @w
r.c-p
#$&l%!#~wI Lf-c @wm iv ‘~_WWflY~~ ..II(
. T._l_T
w$~Yqvjw+j%Y-
_~,~_r~~~_~
~(.
I
71 --T I1’~-Tml”
Fig. 3. 27 min of polygraphic recording (infant 9B) to show cessation of PB as tonic activity builds up at the beginning of state 1. Transition point from state 2 to state 1 is indicated by a, from state 1 to state 2 by b. Oscillation in breathing rate during PB is clear in respiratory rate signal (moving window counter technique, window = 7.5 s). Note presence of tonic activity throughout the state 1 epoch. In this and subsequent compressed records individual breaths cannot be visualized. PB breathing bursts are clearly visible.
52
before and remained elevated during the ensuing epoch of continuous regular breathing. A TcPO, measurement was available for analysis in the case of 20 Type I transitions. A representative example of the TcPO, pattern associated with a typical transition is illustrated in Fig. 4A. In general, TcPO, levels oscillated slightly when breathing was periodic. As PB damped out and tonic activity developed, the TcPO, rose progressively. The onset of the TcPO, rise usually lagged the first indication of tonic activity by about ten seconds, a delay attributable in part to the response time
diaphragy
impedance
Fig. 4. Changes in TcPO, related to breathing pattern changes. In (A) TcPO, falls during IPB, oscillating slightly. It rises as tonic activity in the diaphragm develops and the breathing pattern becomes continuous. This infant, 9A, was recorded in a neonatal intensive care environment. The impedance respiration signal comes from a standard monitor (Hewlett-Packard). In (B) IPB resumes after a general movement early in state 2. TcPO, is slightly lower during PB. State transition points indicated as in Fig. 3.
53
of the PO, measurement system. TcPO, often minutes even after tonic activity had stabilized.
continued
to increase
Switching between continuous and periodic breathing within state I If regular continuous breathing had been established, switching
heart
to PB only
rate
B thermistor
heart
for several
i
a
rate
180
I
150
-1
log10
~4llNlH~l ~TTWTT-~~~
I -7 rr-r
-T--I
min
Fig. 5. (A) 33 min of polygraphic record (infant 5) showmg unmterrupted PB throughout a complete 1 epoch. Transition points as in Fig. 3. Tonic activity develops 6 min into the state in the intercostal minimal in the diaphragm. (B) Another state 1 epoch in the same infant (no. 5) showing switching PB at the state 2 to 1 transition as tonic activity reaches its maximum level. At the transition to state resumes as tonic activity falls. Transition points as in Fig. 3.
state but is off of 2 PB
54
occurred following phasic events. This occurred on 36 occasions in this material. Such switches always followed sighs associated often with startles, and less often with longer general movements. Tonic EMG activity sometimes dropped after the phasic event, a phenomenon not attributable to a change in posture. 18 of these bouts of PB (50%) involved seven or fewer cycles. One such bout is shown in Fig. 7. The EMG and thermistor signals during these short bouts revealed that the apneic periodic pattern faded gradually into an amplitude-modulated non-apneic pattern and finally into a non-oscillating regular pattern again. During this sequence, the
Fig. 6. Three 35-min samples of polygraphic recording from infant 11. (A) PB continues throughout a complete state 1 epoch, except for 3.5 min at the beginning of the state. despite the development of tonic activity in the diaphragm. Intercostal activity is artefactually low because the infant lay in a lateral position with the upper arm flexed across the chest, a posture which is associated with unsatisfactory intercostal EMG recording. Periodic heart rate oscillations are marked. (B) Tonic EMG activity in this state 7 , 4;h is normal and breathing is continuous throughout the state. IPB begins early in state 2. Posture supine. (C) PB throughout a state 1 epoch despite tonic activity in the diaphragm. Intercostal activity artefactually low, as in A. Heart rate oscillations during PB prominent. Note; this infant had an absent corpus callosum and had evidence of dissociated states, such as in Figs. 6B and C the development of tonic activity in the diaphragm 6 min before the state 2 to 1 transition. The EEG was also abnormal (not shown).
55
level of tonic activity rose and stabilized again. Although not illustrated, TcPO, levels were often slightly higher immediately after the sigh triggering these bouts of PB. Thereafter the TcPO, fell gradually during the early cycles in the bout, oscillating slightly. As tonic activity began to build up again and the PB pattern damped out, TcPO, rose again. The other 18 bouts of this type were longer, the number of cycles varying from 10 to 58. The longest bouts all spanned the transition from state 1 to state 2. The two most instructive examples are illustrated in Fig. 8. In the state 1 illustrated in Fig. 8A the eventual return to continuous breathing coincided with reestablishment of a high level of tonic activity. On the other hand, in the instance shown in Fig. 8B tonic activity was higher at one point during RPB than during the preceding regular continuous breathing. Respiratory pauses were shorter and there were more breaths per burst when tonic activity was high than when it was low or absent. At the very end of state 1, tonic activity normally disappears before the breathing pattern changes from regular to irregular. There was no consistent relationship between the timing of the disappearance of tonic activity and an eventual resumption of PB. There was likewise no consistent relationship evident between TcPO, levels and breathing rhythm changes at this time in the four infants in whom TcPO, was measured.
thermistor
intercostal
10 set Fig. 7. A sigh in state 1 followed but rises again as the respiratory
by a bout of PB. Note that tonic activity oscillation damps out. Infant 7.
in the diaphragm
falls initially
lb
56 A
thermistor
,
11,
,r,,r.‘,,,““.“-‘.
r,..
,‘..’
1 ....“.
1
.
I
I
,
E
120 150
1 60 30 0
intercostal
7
71
log 10
..
I
log10
I
I
I
I
II
I
II
11
”
”
”
”
”
min
thermistor
heart rate
150 120 60
resp. rate
30
E 0
I
log10
log10 I Fig. 8. (A) Infant 1. 21 min extract from a polygraphic recording showing switching from continuous to periodic breathing following a sigh in state 1. Tonic activity is slightly lower after the sigh in the diaphragm EMG and shows a falling trend. A later sigh plus general movement is followed by a further drop in tonic activity which then builds up again in association with restoration of a continuous breathing pattern. PB starts again following the next sigh and remains evident as tonic activity decays at the state 1 to 2 transition. (B) Infant 5. A similar compressed polygraphic record as in A. PB is triggered by a sigh and continues through the state 1 to 2 transition. Tonic activity levels in intercostal and diaphragm show both related and independent fluctuations. PB breathing bursts are longer and pauses shorter when tonic activity is high.
57
Discussion In this group of neonates, the oldest of whom was six weeks post-term, most PB bouts were short although occasional infants breathed periodically for up to an hour at a time. Despite the heterogeneity of the group, which precludes among other things any study of developmental aspects of PB, it is interesting that the average cycle length of 16 s is the same as the oscillation in non-apneic breathing found by Waggener et al. [29]. It seems worthwhile drawing attention again to the fact, previously pointed out [23,25], that the pattern of PB may be irregular or regular. That an experienced observer can as reliably distinguish between irregular and regular patterns of periodic breathing as between irregular and regular non-periodic continuous breathing is substantiated by the statistical differences listed in Table V. It seems that PB must be viewed as reflecting the expression of a respiratory system oscillation superimposed on the basic modulation in breathing rhythm associated with the two sleep states. In infants breathing non-periodically (or continuously) in sleep, two main differences in respiratory muscle EMG activity have previously been described between irregular breathing in state 2 and regular breathing in state 1 [19,25,26]. In state 2 sustained tonic activity is absent in both intercostal and diaphragm EMGs. Intercostal inspiratory activity is generally low but variable. Tonic activity builds up at the onset of state 1 in both intercostal and diaphragm EMGs. (Whether the pan-expiratory ‘tonic’ component in the diaphragm signal really originates from the diaphragm is open to question. Arguments for and against a true diaphragmatic origin have been advanced [10,18,20]. This will not be gone into further here since the exact source of the measured ‘tonic’ activity is not crucial to the significance of the observed relationships found in this study.) Intercostal inspiratory peak activity is higher and more consistent in state 1 than in state 2, while diaphragmatic inspiratory peak activity is correspondingly lower in state 1 than state 2. In the group of infants reported here, the EMG features during IPB were essentially as described above for irregular continuous breathing in state 2 except that the oscillation in respiratory amplitude was added. Tonic EMG activity was less consistently present during sustained RPB than during regular continuous breathing. The fact that PB can remain regular throughout what is clearly a state 1 epoch despite an absence of tonic activity, means that the regularity of the pattern per se cannot be the result of mechanical or chemical changes secondary to increased tonic activity. This lends support to the concept that central neural mechanisms and not peripheral reflexes are responsible for the patterning of (periodic) breathing in sleep into irregular and regular types. Animal experiments strongly suggest this, since elimination of all peripheral afferent information in dogs does not abolish the irregularity of breathing in REM sleep [22]. In these infants there was a consistent relationship between the development of tonic activity in the respiratory muscles at the transition from state 2 to state 1 and damping out of existing PB. This occurrence is reflected in the lower incidence of PB in state 1 than in state 2 in nine of the 13 infants. In the course of state 1, PB bouts interrupting continuous breathing were triggered by sighs or sighs plus generalized
58
movements, usually startles. Fleming et al. [5] have used the respiratory response to sighs as a way to estimate respiratory stability, measuring the damping coefficient and oscillatory period of the response. In the present study short PB bouts of this type were usually characterized by a transient drop in tonic EMG level. Damping out of the respiratory oscillation was typically accompanied by a renewed rise in tonic activity level and in TcPO,. The fact that the apparent link between tonic respiratory muscle activity and the switching off of periodic breathing is strongest at the beginning of state 1 and more variable later in the state suggests a change in sensitivity of control mechanisms in the course of state 1. That other unidentified factors must play a role in switching PB on and off can be concluded from the fact that on three occasions (involving two infants) PB persisted throughout state 1 despite an apparently normal build up of tonic diaphragmatic activity. A possible hypothesis to explain the observed relationship between tonic EMG changes and switching off of PB is that an increase in tonic respiratory muscle activity stabilizes the respiratory pump, thereby increasing thoracic gas volume and oxygen stores and leading to a reduction in tidal alveolar gas oscillations. The end result is a decrease in gain in the peripheral chemoreceptor control loop with consequent damping out of respiratory oscillations. Our observations that TcPO, rises as tonic activity builds up and respiratory oscillations damp out is consistent with this theory. So also are the observations of Lopes et al. [16] on the importance of diaphragmatic tonic activity in maintaining lung volume in premature newborns. Experimental administration of oxygen abolishes periodic breathing in preterm infants, although high concentrations may be required [3,17]. Perhaps what we observe is similar, the stability of the respiratory control system responding to normally occurring changes in blood gas tensions caused by spontaneous changes in neuromuscular activity. In this regard the relative paucity of TcPO, measurements and lack of PCO, measurements in this study limits further speculation along these lines. This study suggests that control of tonic activity in the respiratory muscles is a key factor governing the stability of the respiratory system in state 1, at least in early infancy. The neural mechanisms governing the level and pattern of tonic activity in state 1 need to be elucidated. The possibility that excessive amounts of PB in state 1 may reflect a defect in mechanisms controlling muscle tone in sleep deserves further investigation. Refined non-invasive EMG techniques such as those applied in the present study are valuable in this type of research. Acknowledgements The author is grateful to MS Y. Lems for carrying out the statistical analyses and preparing illustrations. The constructive help of Professor H.F.R. Prechtl is gratefully acknowledged. L.A. van Eykern developed the technical facilities which made this work possible. This research is supported by grant no. 13-51-91 from the Foundation for Medical Research Fungo, which is subsidized by the Netherlands Organization for the Advancement of Pure Research (ZWO).
59
References
1 Brady, J.P., Ariagno, R.L., Watts, J.C., Goldman, S.L. and Dumpit, F.M. (1978): Apnea. and aborted sudden infant death syndrome. Pediatrics. 62, 686-691. 2 Chernick. V., Heldrick, F. and Avery, M.E. (1964): Periodic breathing of premature Pediatr.. 64, 330-340.
hypoxemia infants.
J.
3 Fenner, A., Schalk. U.. Hoenicke, H., Wendenburg. A. and Roehling. T. (1973): Periodic breathing in premature and neonatal babies: incidence, breathing pattern, respiratory gas tensions, response to changes in the composition of ambient air. Pediat. Res.. 7. 174-183. 4 Finkel, M.L. (1975): Activity of respiratory muscles in newborn infants during wakening and sleep. J. Evol. B&hem. Physiol.. 1. 92-95. 5 Fleming, P.J., Goncalves, A.L., Levine, M.R. and Woollard. S. (1984): The development of stabihty of respiration in human infants: Changes in ventilatory responses to spontaneous sighs. J. Physiol.. 347. l-16. 6 Flores-Guevara, R., Plouin, P., Curzi-Dascalova, L., Radvanyi, M.-F., Guidasci, S.. Pajot. N. and Monod. N. (1982): Sleep apneas in normal neonates and infants during the first 3 months of life. Neuropediatrics suppl, 13. 21-28. 7 Guilleminault, C., Ariagno, R., Korobkin, R., Nagel, L., Baldwin, R., Coons, S. and Owen, M. (1979): Mixed and obstructive sleep apnea and near-miss for sudden infant death syndrome: 2. Comparison of near miss and normal control infants by age. Pediatrics, 64, 882-891. 8 Haddad, G.G. and Mellins, R.B. (1983): Cardiorespiratory aspects of Sids: An overview. In: Sudden Infant Death Syndrome, pp. 357-374. Editors: Tildon, J.T., Roeder, L.M. and Steinschneider, A. Academic Press, Inc., London-New York. 9 Hagan, R., Bryan. A.C.. Bryan, M.H. and Gulston. G. (1976): The effect of sleep state on intercostal muscle activity and rib-cage motion. Physiologist 19. 214. 10 Harding, R., Henderson-Smart. D.J., Johnson, P. and McClelland. M.E. (1979): Posturally related tonic activity recorded from the peripheral diaphragm in awake and sleeping lambs. J. Physiol. 292, 57p. 11 Henderson-Smart, D.J. and Read, D.J.C. (1979): Reduced lung volume during behavioural active sleep in the newborn. J. Appl. Physiol., 46, 1081-1085. 12 Hoppenbrouwers, T., Hodgman, J.E., Harper, R.M., Hofmann, E., Sterman, M.B. and McGinty. D.J. (1977): Polygraphic studies of normal infants during the first six months of life: III. Incidence of apnea and periodic breathing. Pediat.. 60, 418-425. 13 Kalapesi. Z., Durand, M.. Leahy, F.N., Cates, D.B., MacCallum, M. and Rigatto, H. (1981): Effect of periodic or regular respiratory pattern on the ventilatory response to low inhaled CO2 in preterm infants during sleep. Am. Rev. Respir. Dis., 123, 8811. 14 Kelly, D.H. and Shannon, D.C. (1979): Periodic breathing in infants with near-miss sudden infant death syndrome. Pediatrics, 63, 355-360. 15 Khoo. M.C.K., Kronauer, R.E.. Strohl, K.P. and Slutsky, A.S. (1982): Factors inducing periodic breathing in humans: a general model. J. Appl. Physiol. Respir. Environ, Exercise Physiol.. 53. 644659. 16 Lopes, J., Muller, N.L., Bryan, M.H. and Bryan, A.C. (1981): Importance of inspiratory muscle tone in maintenance of FRC in the newborn. J. Appl. Physiol., 51, 830-834. 17 Monin, P., Vert, P., Andre, M. and Vibert, M. (1979): Transcutaneous PO2 monitoring (TcP02) in the newborn during apneic spells, convulsions, cardiac catheterizations and exchange transfusions. In: Continuous Transcutaneous Blood Gas Monitoring. Birth Defects: original article series, Vol XV. no. 4, pp. 469-491. Editors: A. Huch. R. Huck and J.F. Lucey. Alan P. Liss, Inc., New York. 18 Muller, N., Volgyesi, G., Becker, L.. Bryan, M.H. and Bryan. A.C. (1979): Diaphragmatic muscle tone. J. Appl. Physiol.: Respir. Environ. Exercise Physiol. 47, 279-284. 19 O’Brien, M.J., Van Eykern, L.A. and Prechtl, H.F.R. (1980): Diaphragmatic intercostal and abdominal muscle tonic EMG activity in normal and hypotonic newborns. In: Ontogenesis of the brain, Vol. 3. Proceedings of the International Symposium Neuroontogeneticum Tertium, Charles University, Prague.
471-479.
60 20 O’Brien, M.J., Van Eykern. L.A. and Prechtl, H.F.R. (1983): Monitoring respiratory activity in infants - a non-intrusive diaphragmatic EMG technique. In: Non-invasive Physiological Measurements, Vol. 2, pp. 131-177. Editor: P. Rolfe. Academic Press, London. 21 Parmelee, A.H., Stern, E. and Harris, M.A. (1972): Maturation of respiration in prematures and young infants. Neuropadiatrie, 3, 294-304. 22 Phillipson, E.A. (1978): State of the art: Control of breathing during sleep. Am. Rev. Respir. Dis.. 118, 909-937. 23 Prechtl, H.F.R. (1972): Apparative oberwachung physiologischer Parameter post-partum. In: Perinatale Medizin, Band II, pp. 216-224. Editors: E. Saling and F.J. Schulte. Georg Thieme Verlag. Stuttgart. 24 Prechtl, H.F.R. (1974): The behavioural states of the newborn infant (a review). Duivenvoorde Lecture. Brain Res., 76, 185-212. 25 Prechtl, H.F.R., Van Eykern, L.A. and O’Brien, M.J. (1977): Respiratory muscle EMG in newborns: a non-intrusive method. Early Hum. Dev., 1, 265-283. 26 Prechtl, H.F.R., O’Brien, M.J. and van Eykern, L.A. (1979): Neonatal breathing in different states of sleep and wakefulness. In: Central Nervous Control Mechanisms in Breathing, pp. 443-455. Editors: C. von Euler and H. Lagercrantz. Pergamon Press, Oxford. 27 Rigatto, H. and Brady, J.P. (1972): Periodic breathing in preterm infants. I. Evidence for hypoventilation possibly due to central respiratory depression. Pediatrics, 50, 202-218. 28 Scholten, C.A. and Vos, J.E. (1982): Comparative investigation of the mathematical properties of some descriptors for biological point processes: examples from the human newborn. Med. Biol. Eng. Comput., 20, 89-93. 29 Waggener, T.B., Frantz III, I.D., Stark, A.R. and Kronauer, R.E. (1982): Oscillatory breathing patterns leading to apneic spells in infants. J. Appl. Physiol. Respir. Environ. Exercise Physiol., 52, 1288-1295.