Sleep, 1(4):393-421, 1979
© Raven Press, New York
Sleep Apnea in Normal Kittens
Dennis J. McGinty, Mark S. London, Theodore L. Baker,
Michael Stevenson, Toke Hoppenbrouwers,
Ronald M. Harper, M. B. Sterman, and Joan Hodgman
Veterans Administration Medical Center, Sepulveda, California; University of California,
Los Angeles, California; and Los Angeles County -University of Southern California
Medical Center, Los Angeles, California
Summary: Apneic episodes in normal 10-, 20-, and 40-day-old kittens were
assessed with polygraphic recordings. End expiratory apneas, usually preceded by somatic activity and/or augmented breaths, with durations less than
10 sec were observed in quiet sleep, active sleep, and transitions between
states in all age groups. The highest apnea density was found at state transitions. Heart rate decelerations occurred before, during, and following apneas,
but decelerations were not related to apnea duration. Combined central and
obstructive components were associated with 9% of apneas in normal kittens.
Key Words: Sleep apnea-Sudden Infant Death Syndrome-State
transitions-Augmented breaths-Development.
Repetitive apneas during sleep in adults have been associated with a clinical
syndrome symptomized by diurnal somnolence, pulmonary hypertension, cor
pulmonale, and in some cases, sudden death (Gastaut et aI., 1966; Lugaresi et aI.,
1968; Miller and Granada, 1974). Apneas during sleep have also been implicated as
a contributing mechanism in the Sudden Infant Death Syndrome (SIDS). SIDS
victims are typically discovered in their cribs following a period of presumed sleep
(Bergman et aI., 1970). Stein schneider (1972, 1975) reported that infants who were
subsequently victims of SIDS exhibited frequent short apneic episodes during
sleep in the laboratory. Further, the incidence of apneas was increased during
periods in which babies had minor upper respiratory infections. Such infections
are often precursors of SIDS. In addition, the hypoxic or hypoxemic stimulus
presumed to cause histological changes seen in SIDS victims could have resulted
from sleep apnea (Naeye, 1973, 1974). Finally, certain infants classified as
"near-miss" for SIDS were found to exhibit apneas caused by upper airway
obstruction, similar to the pathological apnea of adults (Guilleminault et al., 1975).
Those observations support the hypothesis that repetitive sleep apnea and associated hypoxia may lead to sudden death in infants.
Accepted for publication May 1979.
Address reprint requests to Dr. McGinty at VA Medical Center (lSIA3), 16111 Plummer Street,
Sepulveda, California 91343.
393
394
D. J. McGINTY ET AL.
On the other hand, apneic episodes during sleep also characterize normal infants (Gould et aI., 1977; Hoppenbrouwers et aI., 1977) and adults (Guilleminault
et aI., 1976). The parameters distinguishing normal and pathological apneas in
infants have not been clearly established. Studies concerned with apnea in normal
infants during the 2-4 month age range of peak incidence of SIDS have appeared
only recently. Since studies in experimental animals appear to have considerable
promise in elucidating control of apnea, (Orem and Dement, 1976), description of
apnea patterns in normal animals is also needed.
The present report describes the incidence and characteristics of apneas in
normal kittens at three postnatal ages. In this report we described the frequency,
duration, and temporal patterns of spontaneous apneas in relation to sleep states
and the patterns of respiration, heart rate (HR), electro myographic activity
(EMG), and eye movements (electro-oculogram, EOG) accompanying apnea. Our
study uses analytic approaches which are very similar to those applied in parallel
studies of apneas in human infants (Hoppenbrouwers et aI., 1977, 1978).
METHODS
Thirty kittens (Felis catus) were derived from a laboratory breeding colony and
ranged in weight from 78 to 122 g at birth. Subjects were randomly distributed into
three age groups (10-, 20-, and 40-day-olds), each containing five males and five
females. Subsequently, a female in the 10-day-old group was replaced by a male
due to a poor respiratory recording. Eighteen kittens (6 kittens at each age) were
used to derive parametric apnea frequency data from standard 12 hr polygraphic
recordings. Twelve additional kittens were studied (4 kittens at each age) for an
8-16 hr period in order to assess the incidence of obstructive apneas.
Forty-eight to 72 hr prior to recording, the kittens were surgically prepared with
chronic electrodes under sodium pentobarbitol (Nembutal, 15-40 mg/kg) anesthesia supplemented with halothane (Fluothane) when needed. Two stainless steel
machine screws (1.6 mm) with attached lead wires were threaded through the skull
on each side of the midline over the sensorimotor cortex for electroencephalographic (EEG) recording. Enamel insulated stainless steel wires (175 /-tm) with an
exposed 2 mm section at the tip were slipped subcutaneously to a position immediately posterior to the eye for detecting eye movements and into the dorsal neck
muscles for recording EMG. Electrocardiographic (EKG) recordings were obtained with pairs of gold-plated fish hooks (no. 24) which were hooked into the
intercostal muscles just above the sternum, 5 -10 mm on either side of the midline
and at the same rostrocaudal level on the back, left, and right of the vertebral
column. Respiration was measured by means of a 0.33 mm diameter, 100,0000,
model 51A30 Veco thermistor suspended in front of one naris. The thermistor and
its lead wires were supported and protected by a stainless steel tube which was
fitted along the bridge of the snout. After blunt dissection of the cutaneous and
abdominal oblique muscles, the diaphragm was exposed from below in 12 kittens.
A 30 gauge stainless needle containing a pair of 62 /-tm Formvar wires insulated
with 10 mm exposed gold-plated tips was slipped through the diaphragm and
withdrawn. The 62 /-tm wires were retained in the muscle sheet by their hooked
tips according to the method of Basmajian and Stecko (1962). Similarly, a 30 gauge
Sleep. Vol. 1. No.4. 1979
SLEEP APNEA IN THE KITTEN
395
needle holding pairs of 62 /Lm wires was forced through the lateral wall of the
thyroid cartilage or between thyroid and arytenoid cartilage and withdrawn, leaving wires for recording intrinsic laryngeal EMG activity. A few EMG recordings
which were contaminated by nonspecific muscle activity were excluded. All lead
wires were routed subcutaneously and collected on top of the head and soldered
to an ultraminiature Winchester 14-pin male connector. EEG electrodes and electrical connections were covered with Caulk Grip Cement and Teets Denture Material. Kittens were given Combiotic (20,000 units) following surgery and 48 hr
postoperatively. A topical antibiotic was also used.
Females and their litters (mean size, 4.8 kittens) were housed together in standard cages (91 x 76 x 76 cm) except for the duration of surgery and the period of
polygraphic recording. A 14 hr light, 10 hr dark cycle was maintained in the colony
with the dark period beginning at 19.00 hr standard time. Food and water were
available ad libitum. Polygraphic recordings were carried out in a shielded
wooden chamber (58 x 71 x 81 cm) with an observation window (61 x 41 cm). A
shallow plastic box containing bedding material was provided for the mother and
litter. The mother had access through an elevated opening to an adjacent cage (61
x 46 x 81 cm) containing food, water, resting sites, and a litter pan. Temperature
was maintained at 25 + 3°C, and room illumination was maintained on the same
schedule as the maternal colony. During recordings, the kitten was attached to a
light, flexible cable suspended from the top of the recording cubicle by an elastic
material. This allowed the kitten unrestricted movement and nursing opportunities.
Continuous 12 hr polygraphic records were begun between 19.00 and 20.00 hr.
The polygraphic signals, left and right EEG, EOG, EMG, and EKG, and respiration, together with a Slow Code-Type B with a 30 sec interval, were recorded on a
16-channel Grass model 78B polygraph and simultaneously stored on a 14-channel
Sangamo Sabre IV analog tape recorder. An IRIG E time code with a 10 sec
interval was recorded on tape only.
The polygraphic paper record was subjected to state classification by identifying each successive minute as waking (W), quiet sleep (QS), active sleep (AS),
transitional (T). Waking was identified by the presence of tonic and phasic EMG
activity and eye movements at a rate of more than 2/min. Active sleep was also
recognized by phasic EMG activity and eye movements but was distinguished
from W by the absence of tonic EMG activity and a much lower respiratory rate.
Quiet sleep was identified by the absence of phasic EMG activity and eye movements (frequency less than 2/min). The onset and offset of Wand AS epochs were
specified at the time of the first and last eye movements or phasic EMG events.
Minimum state epoch duration criteria were 24 sec for QS and AS and 12 sec for
W. Transitional minutes contained criterion epochs for two or more states. Minutes containing artifacts severe enough to preclude scoring were called Unknown.
Apneas were defined as a cessation of respiratory air flow that exceeded three
times the typical QS breath-to-breath interval for kittens at each age. These
criteria were as follows: at 10 days, ~4.4 sec; at 20 days, ~5.0 sec; and at 40 days,
~6.4 sec. The time of occurrence of each apnea as well as correlated changes in
other polygraphic variables were noted. Details of the classification and statistical
treatment of data are provided with the results.
Sleep, Vol. 1, No.4, 1979
396
D. 1. McGINTY ET AL.
All polygraphic signals were digitized on a laboratory computer (Mason et al.,
1973). After the time of onset and termination of each apnea were identified by an
operator, the computer calculated median, minimum, and maximum instantaneous heart rate (HR) values and integrated somatic activity values for several
intervals before, during, and following each apnea and provided continuous calibrated plots of these parameters in relation to the respiratory signal. Maximum
HR decrements were calculated by comparing the rate derived from the maximum
beat-to-beat interval during or within 32 sec following the apnea with the median
HR during a 58 sec period beginning 32 sec after the apnea. This postapnea HR
base line was chosen because apnea-related HR minima usually occurred after the
discrete somatic events which demarcate the associated state transitions or interruptions.
RESULTS
Several examples of apneic episodes in the kitten are shown in Fig. 1. All
apneas counted represented distinct pauses in the respiratory patterns rather than
long breaths and were observed during W, QS, AS, and during state transitions.
Apneas beginning in QS (Fig. lA-C), W (Fig. ID), and AS (Fig. IE-H) were
associated with a variety of correlated events in other polygraphic parameters. (1)
While apneas were sometimes unrelated to somatic activity (Fig. IA), the majority
were preceded by brief (Fig. IB,C) or more sustained (Fig. ID) bursts of neck
EMG activity or by bursts of rapid eye movement (REM) in AS (Fig. IF). If the
preceding EMG activity exceeded 12 sec in duration, the epoch was classified as
W. Apneas occurring in relation to transitions between states were classified as
transitional apneas in certain analyses presented below. Thus Fig. ID represents a
W-QS transitional apnea. (2) Many apneas were preceded by augmented breaths
(Fig. IA,C,D,H). (3) Distinct HR slowing could be found preceding (Fig. IF),
during (Fig. IE), or at the end (Fig. ID) of apneas. Heart rate acceleration sometimes preceded apneas. A quantitative analysis of these apnea-associated
phenomena is presented below.
Although apneas in AS were usually preceded by rapid eye movement (Fig. IF),
the temporal correlation between eye movement and the onset of the apnea was variable (compare Fig. IF-H). On the other hand, eye movements were usually absent for varying periods following AS apneas (Fig. IF), and in some cases AS
apneas were followed by QS (Fig. IG) or arousal from sleep (Fig. IH) and were
also classified as transitional apneas.
Classification and Frequency
Apneas were classified as T, QS, AS, or W in each subject according to the state
preceding and following the apnea as noted above. These data are summarized in
Table 1. It should be noted that there were large individual differences between
kittens in apnea frequency at all ages; the overall frequency of apneas ranging
from 5 to 85. The overall number of apneas was similar in the three age groups.
These data confirm the concept that virtually all apneas occur during sleep, al-
Sleep, Vol. 1, No.4, 1979
E
Eoe
EMe
EKe
il l lil ,II,lili lil l l:,:I;:,;I:I,;:IH;;ll lil l;;il;i;i,I,lli,li l :II;II;IIItI,ll l l l ilil l lil i l l lil 111;lilm
RESP
F
" "
c
J~'tt!J~MI('iI!':~~J,I~~~,
~t\
c
••
'1!'!"II'II'II""I"'I"flill'II"I!f"IlI~IIII"''''I'11p'III"I,HlflJJIIJUlIllUIll
i i ' I ,I '
•"I
I, I
, I ~,
'
o
\/ I'
H
I
.....
. . . . . f• • •
20 SEC
FIG. 1. Examples of polygraphic recordings showing apneas during QS and AS and at state transitions. The types of apneas described in this figure are as follows: (A) QS apnea with no detectable
variation in EEG, EMG, and EKG; (B) clustering ofQS apneas with EOG and EMG activity preceding
second apnea; (C) postarousal apnea during QS; (D) T apnea from sustained arousal to QS; (E) AS
apnea with no EMG activity, preceding EOG activity, and sustained heart rate deceleration; (F) AS
apnea with preceding rapid respiration, skipped heart beats, and EOG activity; (G) AS apnea which is
followed by transition to QS; (H) AS apnea preceded by skipped beats and followed by arousal. D, G,
and H were classified as T apneas. A, C, D, and H were preceded by augmented breaths.
Sleep, Vol. I, No.4, 1979
D. 1. McGINTY ET AL.
398
TABLE 1. Individual subject apnea frequencies
State
Group
Kitten
JO Day
I
2
3
4
5
6
X
20 Day
X
0
0
2
4
4
JOa
3.3
7
S
9
10
II
12
X
40 Day
QS
13
14
15
16
17
IS
6a
lOa
Sa
J3a
7
25 a
AS
I
4
3
13
22
15"
9.7
2
3
0"
2"
7"
22"
W
T
2
3
0"
3
I"
6"
2a
ff
8"'
11a
15a
14a
Total
5
J3
J3
31
42
45
2.5
9.3
24.S
0
0
0"
2"
5"
9"
3
2
29 a
II
15
IS
30
37
S5
lOa
13 a
Isa
11.5
6.0
2.7
12.5
32.7
5
4
15
24
17
24
0
I
3
I
I"
4"
0
I
0"
1"
4"
0"
2a
4a
6a
14a
16 a
7
JO
24
40
41
44
14.S
1.7
1.0
JO.2
27.7
19"
a p < 0.010.
"p > 0.990.
though exceptions are found in all age groups. Indeed, one 10-day-old kitten had
three waking apneas and only two during sleep.
The age-related changes in the frequency of QS and AS apneas resulted in part
from changes in the proportions of these two states during development. As
reported in previous studies (e.g., Hoppenbrouwers and Sterman, 1975; McGinty
et aI., 1977), AS is the predominant sleep state in lO-day-old kittens, but QS
increased rapidly and AS decreased during development. The frequency counts of
sleep state-related apneas were divided by the total time in each state in order to
determine apnea density. Age group means are shown in Fig. 2. An analysis of
variance (ANOY A) was carried out to assess changes in apnea frequency by state
and age, with individual difference between pairs of values assessed with the
Duncan Multiple Range Test. No significant gender differences were noted for any
state or age, so this factor level was collapsed. Transitional apnea density exceeded that of AS, QS, and W densities at 20 and 40 days of age. Quiet sleep apnea
density exceeded AS and W at 20 and 40 days. Other differences between states
failed to reach significance. Both T and QS apnea density increased between 10
and 20 days. No other developmental changes were found.
Patterns in apnea density were assessed in another fashion. The distribution of
apneas among states in each kitten was compared with the actual proportion of
Sleep, Vol. I, No.4, 1979
399
SLEEP APNEA IN THE KITTEN
25
.2
W AS QS
>~
en
zw
C
~
T
20
15
«
W
Z
a..
10
«
5
10
20
40
AGE IN DAYS
FIG. 2. Apnea densities per 100 min of each state in normal 10-, 20-, and 40-day-old kittens. Apnea
density was greatest at state transitions, least in waking. Quiet sleep exceeded active sleep density at
20 and 40 days.
each state using the binomial expansion. Thus a kitten with 10 apneas and 20% QS
would be expected to have 2 QS apneas. Apnea densities less than or exceeding
the expected values at the 1% confidence level are indicated in Table 1. Transitional apnea density exceeded expected values in all subjects except two 20-dayold kittens with low apnea frequencies. Quiet sleep apnea density exceeded expected values only in five of six 20-day-old kittens and one lO-day-old kitten.
Waking apnea densities were lower than expected by chance in 11 of 18 kittens,
and AS apnea densities were lower than expected in 7 of 16 kittens.
Transitional apneas were further classified according to type of state transition
in which they appeared (W-QS, W-AS, QS-AS, QS-W, AS-QS, AS-W) and expressed in terms of density per unit time (Fig. 3A). The highest rate ofT apnea was
observed in AS-QS and W-QS transitions. Active sleep-quiet sleep apneas increased between 10 and 40 days (p < 0.05). Waking-quiet sleep apneas peaked at
20 days and declined thereafter (p < 0.01). In order to assess the possibility that
the relative density of T apnea types could reflect the incidence of transitions of
each type, we calculated the ratio of T apnea frequency to corresponding
transition-type frequency. This analysis also showed that AS-QS transitions were
most likely to be associated with apneic episodes (Fig. 3B). The density of AS-QS
transitional apnea was found to be significantly greater than other types at all ages
(p < 0.05) and to increase between 20 and 40 days (p < 0.005). No other difference among T apnea densities reached significance. Note that in 40-day-old
kittens, about 40% of AS-QS transitions were associated with an apnea.
Sleep. Vol. I, No.4, 1979
D. J. McGINTY ET AL.
400
.80
40
.LAS-OS
.70
35
.60
30
.50
25
fZ
lJJ
lJJ
~ .40
U
a::
a::
lJJ
Q.
.30
.20
20
15
10
.10
AS-W
.roo AS-W
.r- QS • w
r
OS-AS
r W - AS
.r- QS • w
rQS-AS
L - _ r - -_ _~---_+_......!r=-- W-AS
10
20
AGE
A
IN
[oo·W-OS
r"
~-,------~----~---10
40
DAYS
B
20
AGE
IN
40
DAYS
FIG. 3. A: Transitional apnea densities per 100 min. AS·QS and W-QS apneas had highest absolute
rates. B: The percentage of state transitions of each type associated with apnea. AS-QS transitions
were most likely to be associated with apnea.
Apnea Duration
Table 2 shows the mean duration of apneas of various types in each age group.
Note that since minimum duration criteria for apneas were different at each age,
age comparisons are not appropriate. The most interesting result was that apneas
occurring in different states within an age group did not differ in mean duration;
apneas of each type lasted an average of about 5 sec in lO-day-olds; 7 sec in
20-day-olds; and 8 sec in 40-day-olds. A possible exception was indicated in
lO-day-old kittens, in which W apneas tended to be longer, but the difference
resulted from data from one subject.
A frequency histogram of apneas according to duration is shown in Fig. 4. All
types of apneas were included in the histogram. The majority of apneas were
relatively brief, under 10 sec. Note that the frequency of 6- 10 sec apneas increased from 10 to 20 days and from 20 to 40 days.
TABLE 2. Apnea duration according to classification and age (mean ± SD)
Group
QS
AS
T
W
10 Day
20 Day
40 Day
4.92 ± 0.48
7.56 ± 2.60
7.88 ± 1.24
5.10 ± 0.79
6.74 ± 1.41
8.42 ± 1.48
5.37 ± 1.19
6.88 ± 1.45
7.96 ± 1.02
8.68 ± 5.09
5.80 ± 0.40
7.75 ± .91
Sleep. Vol. I, No.4, 1979
SLEEP APNEA IN THE KITTEN
401
60
50
•
10 DAY
o
20 DAY
/},. 40 DAY
>-
40
U
Z
W
::)
o
El:!
30
LL
20
10
45 49 53 5.7 61
65 6.9 7.3 7.7 8.1 8.5 8.9 93
9.7 10J 105 109 ~II.I
DURATION IN SECONDS
FIG. 4. Absolute frequencies of apneas of various durations in each age group. Virtually all apneas
were less than 7 sec in 10-day-olds and less than 10 sec in 20- and 40-day-old kittens.
Temporal Distribution
Figure 5A shows 3 hr time-of-occurrence records of apneas in samples from the
three groups of kittens. It is apparent that apneas tended to occur in clusters in the
10-day-old kitten, but were well-spaced in the 40-day-olds, while the 20-day-old
kitten exhibited an intermediate pattern. Figure 5B shows the distribution of interapnea intervals in each age group. As suggested by the sample data, there was a
tendency for more frequent occurrence of short interapnea intervals in 10- and
20-day-old kittens. These distributions were fitted to a generalized cumulative
probability distribution (Weibell distribution) and compared using the
Kolmorgorov-Smirnov test for two sample distributions. The distribution derived
from 40-day-old kittens differed significantly from the 10- (p < 0.01) and 20-dayolds (p < 0.10). The proportions of apneas following within 2 min of another apnea
were as follows: at 10 days, 17%; at 20 days, 14%; and at 40 days, 10%.
Correlated Somatic and Respiratory Events
As noted above, a majority of apneas were preceded by a burst of somatic
activity (SA) and/or an augmented breath (AB). Table 3 shows the proportions of
Sleep, Vol. I, No.4, 1979
402
D. 1. McGINTY ET AL.
10 DAY
III
1 HOUR
III
2 HOUR
3 HOUR
2 HOUR
3 HOUR
20 DAY
11111
1 HOUR
40 DAY
I
I
I
1 HOUR
I
2 HOUR
3 HOUR
A
-·-10 DAY
- 2 0 DAY
--_. 40 DAY
48
4
40
36
>-
32
z
28
I
u
w
::l
0
w
0::
u..
24
20
16
12
\
\
8
4
0
2
B
4
6
8
10
LATENCY
12
14
16
18
20
22
24
26
28
~30
TO NEXT APNEA IN MINUTES
FIG. S. A: Sample 3 hr time-of-occurrence records from each age group. Apneas were more likely to
occur in clusters in 10- and 20-day-old kittens. B: Inter-apnea latency histograms of all apneas in each
age group, showing higher frequencies of short inter-apnea intervals in younger kittens. Latencies in
minutes. Absolute apnea frequencies were very similar at each age.
Sleep, Vol. I, No.4, 1979
SLEEP APNEA IN THE KITTEN
403
TABLE 3. Percentages of apneas at each age associated with preceding somatic activity
(SA) and/or augmented breath (AB)
SA + AB
AB only
SA only
No SA or AB
40%
50
65
iO
29
26
9
20
14
23
iO day
20 day
40 day
28
42
55
28
20
36
28
29
7
II
AS
10 day
20 day
40 day
39
35
44
iO
9
33
18
29
33
27
II
II
W-QS
iO day
20 day
40 day
30
78
67
0
0
0
70
21
34
0
0
0
AS-QS
10 day
20 day
40 day
70
71
89
iO
21
9
0
7
0
20
0
3
Sleep state
All
iO day
20 day
40 day
iO
3
QS
8
3
state-related and T apneas associated with one or both ofthese events at each age.
Depending on age, 69-76% of apneas were preceded by SA, 50-88% by an AB,
and 80-97% by either event. There was a decline in the percent of apneas not
preceded by either SA or an AB from 20% at 10 days of age to only 3% at 40 days.
The percent of apneas not preceded by an AB declined from 49% at 10 days to
only 12% at 40 days. The occurrence of both SA and AB preceded a large group of
apneas. Apneas preceded by either event alone ranged from 32 to 40%. Most
significantly, all configurations of apneas could appear in either QS, AS, or AS-QS
transitions. The apparent lack of apneas without preceding SA at W-QS transitions is explained by the definition of these transitions, which are identified, in
part, by the existence of SA preceding the activity. Both SA and an AB were
found most commonly preceding AS-QS transitional apneas (70-89%) and least
commonly in AS apneas (35-44%). The majority (61%) ofapneas not preceded by
either SA or AB was in AS. As noted above this type of apnea becomes rare at 40
days of age.
The temporal features of the SA-AB-apnea sequence are shown in Fig. 6 and
Table 4. The times between the onset of SA and apnea and between the last breath
preceding the apnea and the previous breath were measured in each age group.
Figure 6 also suggests that very similar physiological sequences have been found
to be associated with apneas in human infants (Hoppenbrouwers et aI., 1978).
Generally, apneas must be considered as elements in a sequence of events which
is initially manifest in SA.
Sleep, Vol. 1, No.4, 1979
404
D. 1. McGINTY ET AL.
40 DAY
EOG
KITTEN
----~~~------------------------
EMG
THERMISTOR
8
4 MONTH
EOG
EMG
IMPEDANCE
INFANT
--------~-------------
.'
j\J"J'~J".,f,-J\J-/--N'f~
I
10 SEC.
I
FIG. 6. Typical QS apnea with preceding somatic activity and an augmented breath. Durations from
onset of somatic activity to apnea (A) and of breath-to-breath interval preceding the augmented breath
(B) were measured in each age group.
TABLE 4. Apnea sequence (/
A
Group
(sec ± SO)
B
(sec ± SO)
10 day
20 day
40 day
7.58 ± 4.44
4.55 ± 2.62
5.17 ± 2.41
2.06 ± 0.94
1.96 ± 1.21
2.86 ± 1.04
a A, duration from onset of somatic activity to apnea; B, breath-to-breath interval preceding
augmented breath (see Fig. 6).
Heart Rate Changes
Increments and/or decrements in HR were associated with a majority of apneas.
Increments were invariably related to the SA, which usually preceded apneas
(Fig. 7). Means and ranges of HR decrements are shown in Table 5. The following
results may be noted. (1) Apnea-associated maximum HR decrements of at least
70 beats/min were associated with apneas during QS, AS, or at state transitions in
Sleep, Vol. I. No.4, 1979
SLEEP APNEA IN THE KITTEN
405
THRM
EOG
EMG
300_
EKGR 150 _______________J
_ _ _ _~_ _ _ _ _ _ _ ___
FIG. 7. Computer plot of AS-QS apnea (THRM) and associated eye movement (EOG), somatic activity (EMG), and instantaneous heart rate (EKGR). Such T apneas often had large heart rate decelerations.
all age groups, except AS-QS apneas in 40-day-olds. Decrements exceeding 75%
of the base-line HR were not unusual. (2) HR decrements were smaller in 40-dayold kittens compared with younger animals. (3) Larger HR decrements were associated with T apneas in 10- and 20-day-old kittens. Mean decrements exceeded
80 beats/min for AS-QS apneas in 10- and 20-day-old kittens and for W-QS apneas
in lO-day-old kittens.
Most HR minima occurred in an 8 sec period following the apnea, but 32%
reached a minimum during the apnea, and in several cases the deceleration began
before the onset of apnea. HR decrements were not correlated with apnea duration.
Obstructive Apneas
Obstructive apneas were defined by the occurrence of a distinct burst of diaphragmatic EMG activity, without the usual accompanying nasal air flow (Fig. 8).
In 12 recording sessions, we identified 12 sleep apneas with obstructive components out of a total of 94 apneas, or 13% of total apneas. Obstructions usually
persisted during only one diaphragmatic burst, and never exceeded four bursts in
duration. In 10 of 12 cases obstructive breaths preceded or followed central apneas and could be classified as mixed apneas according to the definition of Gastaut
et al. (1966). These mixed apneas most often occurred in QS. Obstructive breaths
Sleep. Vol. I, No.4, 1979
D. 1. McGINTY ET AL.
406
TABLE 5. Heart rate decelerations associated with apneas
(J
Age group
10 Day
x
State
-48.3
-57.1
-100.4
-89.8
218
221
QS
AS
W-QS
AS-QS
QS HR
AS HR
20 Day
SX
Max
7.4
14.8
18.6
15.4
-109
-147
-188
-184
x
-41.8
-50.0
-67.7
-88.6
210
211
40 Day
SX
Max
8.7
7.3
12.3
11.5
-74
-102
-174
-168
x
-34.2
-41.0
-65.1
-31.3
184
179
SX
Max
4.7
10.2
16.3
4.3
-73
-135
-193
-62
Age differences: t values
Age (days)
All States
QS
AS
W-QS
10 vs. 20
10 vs. 40
20 vs. 40
1.246
3.311'
2.496 b
0.566
1.610
0.772
0.430
0.896
0.718
1.471
1.430
0.127
AS-QS
0.065
3.660"
4.661rl
State differences: t values
State
10 Day
20 Day
40 Day
QS vs. AS
QS vs. W-QS
QS vs. AS-QS
AS vs. W-QS
AS vs. AS-QS
W-QS vs. AS-QS
-0.529
-2.605 b
-2.425 b
-1.827
-1.534
0.439
-0.717
-1.712
-3.233'
-1.236
-2.830"
-1.242
-0.609
-1.823
0.457
-1.253
0.880
2.007
Mean, x; standard error of the mean, SX, and maximum deceleration, Max.
< 0.05.
c
< 0.01.
rl P < 0.001.
a
b
p
p
were more sustained than swallows and could also be distinguished from yawns.
Obstructed breaths were sometimes associated with laryngeal adductor EMG
activity, but this association was variable (see Fig. 8). Visual observation showed
that obstructive events were not associated with mouth breathing. Laryngeal
adductor EMG activity was also observed during the typical apneic pauses described in this report. These events will be described in greater detail in a subsequent report.
DISCUSSION
The objective of this study was a description of apnea in normal kittens monitored under normal conditions. Accordingly, all data were derived from apparently healthy kittens recorded for 12 hr in the presence of mother and littermates.
Evidence of population normality was found in sleep state proportions which
corresponded to those reported in previous studies (McGinty et aI., 1977). Kittens
in the lowest quartile of birth weights were not used. Thus the characteristics of
apneas found in this study are assumed to be reflections of normal physiological
processes.
Sleep, Vol. I, No.4, 1979
SLEEP APNEA IN THE KITTEN
407
EEG
EOG
EMG
LARYNX
DIAPHRAM
• iIIII
i...
..
.......
I~'"
"". '.'
~1~@~i~i~I~I~i~lfi~i~li II HIIIIIII~11 tI~ HIjW'~OO,'lj~~~~~~~~~i
NASALAAAAAAU~A
THERM. Y\j \J \j \j \j
\J ~ ~ ~ \
6SEC.
FIG. 8. Obstructive apnea was defined by diaphragmatic activity without associated nasal air flow.
This example was the longest obstruction seen in normal kittens. Note large heart rate deceleration
typical of obstructive apneas. Obstructive apneas were usually associated with laryngeal adductor
EMG activity.
The following features characterized apnea in the kittens. (1) Almost all apneas
occurred during sleep. (2) All apneas were end expiratory. (3) The frequency of
apneas was extremely variable from subject to subject. The same large variation in
apnea frequency was found in a recent study of apnea in normal human infants
(Hoppenbrouwers et aI., 1977). (4) Apneas occurred most frequently during transition between states. This observation was seen both in the absolute frequency of
apneas in various states and in the distribution of apneas among states within
individual subjects. (5) Most commonly, apneas were preceded by a movement
and a deep breath (sigh) or one of these two events. The percentage of apneas
without these preceding events declined with age to 3% at 40 days and were most
often found in AS. (6) Apneas of all possible configurations of preceding events or
HR decrements occurred in QS and AS and in transition between states. (7) Large
HR decrements occurred during or following apneas and were associated with all
apnea configurations, but particularly with T apneas. Heart rate decrements declined with age and were not related to apnea duration. (8) The average duration of
apneas was similar in all states; virtually all apneas lasted less than 10 sec in 40and 20-day-old kittens and less than 7 sec in 10-day-old kittens. The response of
the peripheral chemoreceptor may facilitate apnea termination, since sensitivity to
hypoxia, but not hypercapnia, is uniform across states (Phillipson and Sullivan,
1978). (9) Apneas with brief transient obstructive components are associated with
13% of apneas. A parallel study of apneas in kittens recorded in isolation from
mother and littermates also showed the consistent relationship of apneas to SA,
AB, and state transitions (Baker and McGinty, in press).
Apneas were usually elements of an ordered sequence which frequently included increased SA, a sigh or AB, a co-occurring variable HR deceleration, and
sleep state transition. However, one or more elements could be missing from this
Sleep. Vol. 1, No.4, 1979
D. 1. McGINTY ET AL.
408
cluster of events, and any ofthese events could occur on its own. These variations
in the movement-sigh - HR deceleration sequence suggest that one event does
not cause another. In particular, since apneas could occur without preceding
sighs, it is probably incorrect to assume that the sigh caused the subsequent
apnea, although a strong inspiratory effort or pulmonary afferents responding to
the augmented breath may contribute to the expiratory pause. We suggest that
these phenomena might be caused by some underlying excitatory process which
occurs periodically. However, each of these manifestations of this excitation may
have a varying threshold for occurrence. The most common manifestation of
excitation would seem to be SA (movement), which is known to punctuate sleep in
several species (Rechtschaffen and Kales, 1968; McGinty, 1971). A state transition occurs less often than somatic activity, and an AB and/or apnea occurs still
less frequently than state transitions. Changes in threshold may also explain the
more frequent occurrence during AS of apneas without any preceding events.
Active sleep is associated with a profound inhibition of motoneuron excitability
(Pompeiano, 1969). Thus the somatic expression of periodic excitation is suppressed, but other events, such as apnea, may still occur. It is notable that rapid
eye movements, which are expected from motor inhibition, often preceded AS apneas. According to this concept, the variable HR decrement associated with apnea
is a consequence or aftereffect of periodic excitation (see below), rather than a
result of apnea. This view is supported by the observation that HR decelerations
W-QS
AS
BEHAVIORAL
STATE
W
QS
NON-SPECIFIC
AROUSAL
RESPIRATION
AS-QS
BRIEF AROUSAL
QS
~lf
I
i
!
I
.I
i
i
r
I•
j~
~
!\. . . .
i~
\.........
h1M~Vl ~V1
FIG. 9. A hypothetic account of high transitional apnea densities and associated heart rate decelerations. Transitions from states with higher to lower central nervous system arousal were associated with
apneas. Transient undershoots in arousal at transitions could defacilitate respiratory neurons and
release vagal afferent tonus. In pathological subjects (dotted lines) changes in arousal at transitions
may be larger or more sustained.
Sleep, Vol. I, No.4, 1979
SLEEP APNEA IN THE KITTEN
409
could occur during, or before, as well as after apneas, and the magnitudes of the
decelerations were unrelated to apnea duration.
The association of sleep apneas with transitional periods between states may
have further significance. The transitions from W to QS and AS to QS were most
likely to precipitate apneas. These state changes have in common the property of a
change from a condition of higher to lower nervous system excitability. Both W
and AS are characterized by a generally higher rate of brain unit discharge, oxygen consumption, and cerebral blood flow as compared with QS (McGinty et aI.,
1974). Further, most apneas not occurring at state transitions are preceded by a
movement which may also correspond to a transient augmentation of cerebral
excitability (Allison and Goff, 1968), followed by a return to a less excitable
condition. We hypothesize that many sleep apneas are a reflection of a decrement
in nervous system excitation, mediated by brainstem reticular arousal systems.
Figure 9 shows a schematic representation of this concept. Included in our concept is the idea that a rapid decrement in reticular excitation is associated with a
transient undershoot in excitability, an "off" response, like that observed in
response to stimulation offset in other brain sites (Hartline, 1938). A decrement in
respiratory drive is a probable consequence of reticular deactivation. The role of
arousal as a respiratory stimulus noted by Fink (1961) has recently been discussed
by Phillipson and Sullivan (1978). The HR decrement following apnea may be
another manifestation of reticular deactivation. Notably, the largest HR decrements also occurred at AS-QS and W-QS transitions.
The relation of apneas to state transitions has not been emphasized in previous
studies on human infants. While species differences may account for this discrepancy, classification procedures used in infant studies could obscure the importance oftransitional periods. Gould et al. (1977) reported the highest apnea attack
rates in indeterminate sleep and active sleep in normal twins at 40, 44, and 52
weeks gestational age and Hoppenbrouwers et al. (1977) reported the highest
apnea rate in indeterminate sleep at 1 and 2 months in low-risk infants. Indeterminate sleep may frequently represent epochs containing transitions between states.
In our studies the sleep state during 12 sec periods preceding and following the
apneic interval was noted. Scoring strategems involving longer epochs, for example, relating apneas to 1 min epochs, tend to underestimate transitional
phenomena.
Repetitive obstruction and mixed apneas associated with severe cases of the
sleep apnea - hypersomnia syndrome of adults also occur at transitions from W to
QS (Krieger and Kurtz, 1978). Thus pathological apneas, like normal apneas,
occur at state transitions. The hypothesis could be stated as follows: sleep apneas,
both normal and pathological, reflect a decrement in nonspecific excitatory drive
on respiratory centers that is particularly manifest at transitions from more excited to less excited states.
The present study has shown that mixed or obstructive apneas may occur in
normal kitten subjects. Pathological apneas in adults leading to severe hypoxemia
are far more frequent, of longer duration, and more consistently obstructive, as
compared with normal apnea. According to our hypothesis, these repetitive
arousals contribute to the pathological sequence by setting the stage for frequent
Sleep, Vol. I, No, 4, 1979
410
D. 1. McGINTY ET AL.
W-QS transitions. Of course, a more fundamental deficit must account for the
failure to maintain airway patency after a normal T apnea period. Current conceptions of upper airway obstructive apnea in adults emphasize relaxation of
pharyngeal or genioglossus muscles as central elements of the mechanism of
obstruction (Harper and Sauerland, 1978; Hill et aI., 1978; Remmers et aI., 1978).
This relaxation is likely to result from loss of central arousal. Stimulation of brain
reticular formation sites corresponding to the arousal system has recently been
shown to facilitate laryngeal abductor EMG activity (Orem and Lydic, 1978), and
it is very likely that other assessory respiratory muscles would be modulated by
the same excitatory system. Many previous studies have shown widespread motor
system activation from reticular stimulation (e.g., Sprague et aI., 1948). Our central hypothesis would apply if subjects with pathological apnea were characterized
by an abnormally rapid, large, or sustained decrement in nonspecific nervous
system arousal following a state transition (Fig. 9).
Orem and Dement (1976) have shown that postsigh apneas in the adult cat may
be associated with sustained discharge of medullary respiratory neurons, indicating that active mechanisms may facilitate this type of apnea. Similarly, we noted
sustained laryngeal adductor EMG activity usually limited to apneic intervals.
These observations would seem to argue against the idea that apneas represent
periods of loss of nonspecific arousal. However, we do not mean to imply that
decrements in arousal are independent of the function of active inhibitory systems. Orem and Lydic (1978) demonstrated mainly bulbar inhibitory as well as
more rostral facilitatory brainstem sites for laryngeal abductors. Brain regions
capable of facilitating QS onset and inhibiting reticular activation have also been
localized in the medulla as well as in the midbrain and forebrain (see McGinty and
Siegel, in press). Thus abnormal sleep onset-related reticular deactivation could
reflect an action of some active inhibitory system.
This study was stimulated by the need to find parameters to distinguish normal
and pathological apnea. While increased apnea frequency, duration, or degree of
obstruction has been noted in near-misses for SIDS infants (Guilleminault et aI.,
1975), significantly reduced apnea frequencies have also been found to characterize some infants at risk (Hoppenbrouwers et aI., 1978). Apnea frequencies are
also greatly reduced in hypoxic kittens (Baker and McGinty, in press). Thus the
reduction in apnea frequencies may be regarded as an indication of an underlying
abnormality. It should be remembered that episodic respiratory failure patterns
characterized by shallow or slow breathing (hypoventilation), rather than apnea,
have been seen in hypoxic kittens (Baker and McGinty, 1977) and adults with
chronic lung disease (Koo et aI., 1975). Since nonapneic respiratory failure is a
possible cause of SIDS, and low apnea rates may characterize infants at risk, we
must look even more closely at the exact parameters which may distinguish normal and pathological apnea. The present data show that, at least in the kitten,
apneas occurring at rates up to 7/hr with durations up to four to five times the
mean QS respiratory interval, with some HR decrements over 50% of the baseline rate, and with occasional obstruction components, should not necessarily be
regarded as pathological. Sleep apnea associated with episodic oxygen desaturation has been seen in a majority of normal (asymptomatic) male hospital workers
Sleep. Vol. I, No.4, 1979
SLEEP APNEA IN THE KITTEN
411
(Block et aI., 1979). Nonpathological apneas in kittens may be recognized by their
duration and consistent relationship to somatic activity, sighs, and state transitions. We recognize that apneas are not homogeneous in origin and that they may
be elicited by a variety of events, including seizures (Schulte, 1977) and laryngeal
stimulation (Sullivan et aI., 1978). Pathological apnea may also reflect an abnormality of the mechanism which terminates apnea. We believe that future studies
should emphasize the sequential events associated with apnea.
ACKNOWLEDGMENT
This research was supported by the Veterans Administration and Contracts
I-HD-4-2810 and I-HD-2-2777 from the National Institute of Child Health and
Human Development of the National Institutes of Health.
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