Chemoreceptor
Function
and Sleep
State
in Apnea
S. Allen Fagenholz, M.D., Kathleen O’Connell, B.S., and Daniel C. Shannon, M.D.
From the Children ‘s Service and the Pulmonary Unit, Massacl,usetts Genera! tiospital, and the Departnzent of
Pediatrics and Medicine, Harvard Medical School, Boston
ABSTRACT. Resting ventilation and ventilator>’ responses to 100% oxygen and to 5% carbon dioxide in air were measured in REM and non-REM sleep in post-neonatal infants. Normal controls were compared to infants with prolonged apnea and to siblings of sudden infant death victims. No significant differences in ventilatory responses were found between the groups. We conclude that apnea may occur in infants whose central and peripheral chemoreceptor activity is normal while they are breathing. Pediatrics, 58:31-36, 1976, APNEA,
SIDS, CARBON DIOXIDE RESPONSE, SLEEP STATES.
Apnea and cyanosis have been noted to occur during sleep in otherwise normal infants and have been implicated in the sudden infant death
syndrome (SIDS).’ SIDS has a peak incidence in the post-neonatal period,2 and an increased mci-dence in some families. Congenital failure of automatic ventilation, Ondine’s curse, has been described in infants34 and the associated carbon dioxide unresponsiveness has been accompanied
by alveolar hypoventilation only during the
non-REM state of sleep.5 Because of these observa-tions we investigated ventilatory responses to carbon dioxide and to oxygen in relation to sleep
state in the post-neonatal period. Infants with
documented apnea (>20 sec) were compared to normal controls and to siblings of SIDS victims.
MATERIAL AND METHODS
Three groups of young infants were studied. The normal controls (No. = 16) were healthy
volunteers. The SIDS siblings (No. = 14) were unaffected infants born to a family in which there had been a death consistent with SIDS by history and, when available, postmortem examination report. All of the infants remained well subse-quent to the study. Affected infants (No. = 10) were referred because of unexplained cyanotic episodes which proved subsequently to be recur-rent apnea of more than 20 seconds in duration, as witnessed by a medically trained observer while the infant was connected to an impedance type apnea monitor. Six patients had prolonged apnea further corroborated by recording of the
impe-dance pneumograph signal from the monitor onto
magnetic tape.’ All affected infants had normal
general physical and neurological examinations. Routine laboratory studies included 12-lead ECG,
EEC, chest X-ray, arterialized capillary blood
gases, urinalysis, and complete blood count.
Further investigations when indicated clinically included lumbar puncture, blood culture, glucose and electrolytes, and special neurological proce-dures. Infants with apnea on the basis of extreme
(Received August 12; revision accepted for publication October 28, 1975.)
Supported by Training Grant HL 05767 from the National Institutes of Health (S.A.F.).
Read in part before the Society for Pediatric Research, Denver, Colorado, April 19, 1975.
EKG
9)
5 sec
NON-REM, AIR NONREM,5%CO2 REM, AIR
E EG
Iioo#uv
(kI/’1rlc
EOG }oov _
PCO2
VE,ml
7
f//I
FIG. 1. The EEC, EOC, end-tidal PCO2, ventilation in milliliters
(,
ml), and impedance pneumograph in one infant. Left panel was recorded during air breathing in non-REM sleep. Note high-voltage slow-wave EEC, absence of eye movements, and regularity of respiration.Middle panel was recorded during 5% carbon dioxide breathing in non-REM sleep. Note that the characteristics of non-REM sleep continue and that PCO2 is elevated and tidal volumes increased.
Right panel was obtained during air breathing in REM sleep. Note low-voltage fast-frequency
EEC, eye movements on EOC, and irregular respiratory frequency and tidal volume.
prematurity, respiratory distress syndrome,
sei-zure disorder, or any other identifiable cardiopul-monary problem were excluded. The protocol was approved by the Human Studies Committee and informed consent obtained from parents in each case.
Ventilation, end-tidal Pco2, EEG, ECG, eye movements by electro-oculogram (EOG), and impedance pneumogram were recorded on all infants in a quiet, darkened room following a normal feeding during natural sleep. Recording
was done on a six-channel polygraph (physio-graph
6, Narco
Bio-Science,
Houston, Tex.) at 5 mm/sec. Topical 5% lidocaine jelly was applied to the nares but no sedation was used. One observer held the infant and noted behavior while the other operated the recording apparatus.The apparatus used to measure minute ventila-tion and alveolar Pco, has been described.7 The nasal pneumotachygraph devised by Rigatto and Brady affords the advantages of low dead space
(0.1 ml) and low resistance (0.3 cm of H9O/liter/ mm). It was employed with a very low range differential pressure transducer (MP-45, Validyne Engineering, Northridge, California), carrier preamplifier (HP-300, Hewlett-Packard, Palo-Alto, California) and resetting integrator. A constant background flow of 3 liters/mm or greater, exceeding the infant’s calculated peak
inspiratory flow rate, was maintained by two-stage regulators and a flow meter (Matheson Gas
Products, Model 604, Rutherford, New Jersey). The flow signal was electrically balanced to an
artificial zero and the infant added to (expired) or
subtracted from (inspired) the background flow, which was electrically integrated to give volume. The volume measurements, determined with a calibrated piston pump respirator (Harvard Apparatus, Model No. 666, Millis, Massachusetts) were linear within 10% from 20 to 40 breaths per minute. For each study the volume per full scale
TABLE I
SLEEP STATES
RESULTS determined from the number of full-scale
deflec-tions per minute. We corrected for the measured flow through the carbon dioxide analyzer and expressed at BTPS per kilogram of body
weight to permit comparison between infants of
different size.
End-tidal Pco2 was measured with an infrared carbon dioxide analyzer (LB-i, Beckman Instru-ments, Fullerton, California) drawing 60 ml/min of expired air from one nasal adaptor through 60 cm of PE9O tubing.
During any period of measured VE the end-tidal Pco, tracing with the best plateau and a slope of less than 10% was chosen. Pco, was determined from a calibration curve constructed
by passing five graded carbon dioxide in air
mixtures through the analyzer. We recalibrated the volume and carbon dioxide channels between each set of measurements.
Ventilatory responses were obtained by
intro-ducing the nasal pneumotachygraph while the infant slept. If sleep remained undisturbed in a well-defined state a baseline period of three minutes breathing room air was recorded (Fig. i)
and then the composition of inspired gas was abruptly changed to either 5% carbon dioxide in air or 100% oxygen. Carbon dioxide responses were obtained over at least three minutes; a
steady state was considered achieved when there
was no further net change in ventilation for 30 seconds. Responses to 100% oxygen were recorded for 30 seconds. After any change in inspired gas composition the infant was given at
least three minutes on room air to recover before
a new baseline was recorded.
The response to 100% oxygen was calculated by
measuring VE for 30 seconds on air and then for
the first 30 seconds on oxygen. The difference was divided by the value of VE on air and expressed as a percentage.
Sleep state was determined from simultaneous recordings of EEG, EOG, and respiratory pattern
from impedance pneumogram, and from direct observation of the infant’s behavior. EEG was recorded from lead FP,-C., using gold cup elec-trodes (Grass Instruments, Qumncy,
Massachu-setts) with full-scale calibration of 100tv. EOG
was recorded from the outer canthi of the eyes using similar electrodes and sensitivity. Both signals were referred to the forehead. Sleep state was scored as non-REM or REM by a four-item
scheme (Table I) modified from Anders et al.” Indeterminate states were not included in the analysis. Sleep state was scored as non-REM when a high-voltage slow or a trace alternant pattern
was seen on EEG, rapid eye movements were
Characteristic REM Non-REM
EEC Low-voltage fast High-voltage slow
EOG (REM) Present Absent
Limb movements Present Absent (or star-ties)
Respiration pat- Irregular Regular tern
absent on EOG, respiration was regular by impe-dance pneumogram (a breath-to-breath interval varying less than 20%), and no body movements
or generalized startles were observed. REM sleep
was scored when EEG indicated a low-voltage
fast pattern, rapid eye movements were present,
respiration was irregular, and limb movements were observed. All sleep states were required to be consistent for three minutes, and all were scored by the same observer.
While the ages and weights for controls, SIDS siblings, and infants with apnea overlapped, there were significant differences in the mean values. At 11.1 ± 1.0 weeks (mean ± SE) the controls
were older than the siblings (5.1 ± 0.8, P < .001
by unpaired t-test) and the affected infants (6.7 ± 0.8, P < .01). The controls at 5.25 ± 0.17 kg were also heavier than the siblings
(3.96 ± 0.26, P < .001) and the affected infants (4.32 ± 0.26, P < 0.01). Table II shows the char-acteristics of the three study groups and the ventilatory responses in each sleep state. Figures
2 and 3 illustrate the ventilatory responses to
carbon dioxide and oxygen in each sleep state for the control group. The unpaired t-test was used to evaluate statistical significance at the P < .01 level for each measurement. Values in Table II
are compared to the corresponding values for the
control group.
Comparing the two sleep states in the control
group, minute ventilation per kilogram (VE, ml/
kg/mm, BTPS) was greater in REM than
non-REM sleep, but this difference was not
TABLE II
CLINICAL DATA
Cont rots SIDS Siblings Affecte d Infants
Data Mean SE No. Mean SE No. P#{176} Mean SE No. P#{176}
Age (wk) 11.1 1.0 16 5.1 0.8 14 <.001 6.7 0.8 10 <.01
Weight (kg) 5.25 0.17 16 3.96 0.26 14 <.001 4.32 0.26 10 <.01
‘K (mI/kg/mm)
Non-REM 211 16 16 199 16.9 14 >20 203 14.4 10 >20
REM 234 88 9 249 20.5 14 >20 222 15.2 9 >.20
Respiratory frequency (breaths per mm)
Non-REM 29.9 1.6 16 34.9 2.4 14 >05 28.8 1.3 10 >20
REM 33.7 2.1 9 41.3 2.0 14 >02 33.8 1.4 9 >20
PCO. (mm Hg)
Non-REM 35.4 0.56 16 36.4 0.6 14 >20 35.9 0.5 10 >.20
REM 34.8 0.71 9 36.5 0.6 14 >05 36.7 1.2 8 >10
Slope (ml/kg/min/mm Hg)
Non-REM 73.0
Carbon
14.9 12
Dioxide Response Curves
44.1 6.7 13 >05 47.0 3.5 9 >10
REM 54.0 20.2 3 48.5 7.4 7 >20 37.3 7.9 9 >10
Intercept (mm Hg at V = 300)
Non-REM 36.4 0.54 12 39.0 0.9 13 >02 37.9 0.7 9 >05
REM 37.7 2.34 3 36.3 0.6 13 >02 38.8 1.3 8 >.20
% change in from air to 100% oxygen
Non-REM -31.0 4.0 16 -44.8 4.0 14 >02 -31.3 6.1 10 >.20
REM 1.3 24.0 7 -24.9 6.8 10 >20 -22.9 9.0 8 >20
OP values refer to comparison between each variable and the corresponding variable in control infants.
change in VE during 30 seconds of 100% oxygen
breathing. There were, however, no significant differences for each sleep state in either baseline values breathing air or in ventilatory responses to carbon dioxide or 100% oxygen between siblings and controls. Likewise, there were no significant differences between affected infants and con-trols.
While the differences did not reach the level of statistical significance, minute ventilation was consistently higher in REM compared to non-REM sleep in each group of infants, and this was almost entirely due to increased respiratory
frequency. At the same time, end-tidal Pco2 was
constant in each group of infants and in each sleep state. There were no consistent differences in either the intercept or the slope of the carbon dioxide response curve during REM compared to non-REM sleep in the three infant groups, nor was the depression of ventilation during oxygen breathing significantly greater in non-REM sleep.
DISCUSSION
We measured peripheral and central chemore-ceptor activity in both sleep states in normal post-neonatal infants, SIDS siblings, and infants with prolonged sleep apnea. Minute ventilation was increased during REM sleep to a level compa-rable to that observed in the newborn by other investigators.”” As in the newborn, this change was due mainly to increased respiratory
freqisen-cy while the mean tidal volume was unchanged.
Increased ventilation without a change in Pco2 implies one of two possibilities: (1) increased dead space ventilation or (2) a proportional increase in both alveolar ventilation and metabolic rate. We have previously observed that an increased carbon dioxide production rate accounts for part of this change.5 This may be a result of the sporadic muscle activity which is a constant feature of REM sleep.”
The slope and intercept of the carbon dioxide
‘:3’ “‘C \ \ -1 . 300 -200 -+20 -. 0-t&J
(-pa
-20-:1: -40 REMI
-4
NON-REM30 35
0
so
so
so
NON-REM40
Pc02
, rnrn/-/q -30 +60TIME, SECONDS
FIG. 3. The percentage of change in ventilation (% change in
VK ) during air and 100% oxygen breathing in 16 normal infants in REM and non-REM sleep. Vertical bars indicate 1 SE. P value for the difference in percentage of change is not
significant.
400 - +40
-- 100% 02
1
AIR
I I I
0 +30
FIG. 2. Ventilation (iKE inl/rnin/kg/BTPS ) at the
simi,lta-neously measured end-tidal PCO. mm Hg in 16 normal infants while breathing air and 5% carbon dioxide during REM and non-REM sleep. Horizontal bars indicate 1 SE. P
values for both the slopes and the intercepts are not significant.
central chemoreceptors and brain buffering of H + ions along with vagal stretch reflexes acting in concert with the medullary inspiratory-expira-tory drive on a lung and thorax with specific mechanical properties. Changes in slope can be ascribed to greater or lesser effects of one or more of these inputs into the respiratory centers or to impaired mechanical properties of the lung, e.g., decreased compliance. The net effects of input on output are the same in REM and non-REM sleep in infants since the intercept and slope are not significantly different. The same is true for adults in REM and intermediate stages of non-REM sleep while deeper stages are associated with an increased intercept and decreased slope.’2
Having used a technique similar to that of Riggato et al,” we can compare the chemore-ceptor responses of his preterm infants at various ages to our post-neonatal infants. Beginning at 28 weeks’ gestation, the slope is 24 ± 7 ml/kg/mmn/ mm Hg and the intercept 47 ± 4 mm Hg and both indices move toward those of our infants by 27 post-natal days. Our data do not elucidate the mechanism(s) responsible for this change.
Our infants with prolonged apnea (>20 seconds) had normal peripheral and central chemoreceptor activity in both states of sleep.
Thus, they do not represent a form of Ondine’s curse, in which carbon dioxide unresponsiveness is associated with hypoventilation in non-REM sleep. Neither do they resemble young premature infants with periodic respiration who have decreased response to carbon dioxide and increased response to 100% oxygen.” It appears that normally active chemical drives to respira-tion can be overriden in vulnerable infants by other mechanisms. Although our data do not support any particular hypothesis for apnea, central chemoreception must be inactivated during the apneic episodes. Possible mechanisms include either hypoxia’5 or stimulation of laryn-geal taste receptors.”’
The group of subsequent siblings of SIDS infants also had normal ventilatory responses. These infants remained well, and comprise a second group of nonapneic infants.
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ACKNOWLEDGMENT
