Respiratory instability during sleep onset.

It has been hypothesized that regulatory control in the respiratory system is state dependent. According to this view respiratory instability during sleep onset is a consequence of repeated fluctuations in arousal state. However, these speculations are based primarily on measurements during stable sleep, not during sleep onset itself. The aim of the present study was to assess changes in ventilation and gas tensions during sleep onset as a function of arousal state. Twenty-one subjects (12 males and 9 females, mean age 20 yr) were assessed over an average of 11.3 sleep onsets. The subject's state was classified as alpha, theta, body movement, or stage 2 sleep, and expiratory tidal volume, minute ventilation, respiratory rate, and end-tidal CO2 and O2 were measured by means of a face mask, valve, and pneumotachograph on a breath-by-breath basis. Respiratory instability during sleep onset was found to be a result of two factors. The first factor was a between-state effect in which transitions from alpha to theta were associated with falls, and from theta to alpha with increases, in ventilation. The magnitude of the change was a positive function of metabolic drive at the time of the state change (as indicated by alveolar PCO2 and PO2 levels). The second was a within-state effect in which ventilation fell during consecutive alpha breaths and increased during consecutive theta breaths. These changes were due to the influence of the relative hyperventilation of the alpha state and the relative hypoventilation of the theta state on metabolic drive.     

Geniohyoid muscle activity in normal men during wakefulness and sleep

Reduction in the activity of upper airway "dilator" muscles during sleep may allow the pharyngeal airway to collapse in some individuals. However, quantitative studies concerning the effect of sleep on specific upper airway muscles that may influence pharyngeal patency are sparse and inconclusive. We studied seven normal men (mean age 27, range 22-37 yr) during a single nocturnal sleep study and recorded sleep staging parameters, ventilation, and geniohyoid muscle electromyogram (EMGgh) during nasal breathing throughout the night. Anatomic landmarks for placement of intramuscular geniohyoid recording electrodes were determined from a cadaver study. These landmarks were used in percutaneous placement of wire electrodes, and raw and moving-time-averaged EMGgh activities were recorded. Sleep stage was determined using standard criteria. Stable periods of wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep were selected for analysis. The EMGgh exhibited phasic inspiratory activity during wakefulness and sleep in all subjects. In six of seven subjects, mean and peak inspiratory EMGgh activities were significant (P less than 0.05) reduced during stages 2 and 3/4 NREM sleep and REM sleep compared with wakefulness. This reduction of EMGgh activity was shown to result from a sleep-related decline in the level of tonic muscle activity. Phasic inspiratory EMGgh activity during all stages of sleep was not significantly different from that during wakefulness. Of interest, tonic, phasic, and peak EMGgh activities were not significantly reduced during REM sleep compared with any other sleep stage in any subject. In addition, the slope of onset of phasic EMGgh activity was not different during stage 2 NREM and REM sleep compared with wakefulness in these subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of chemical and state effects on ventilation during sleep onset

Dunai, Judith, Mal Wilkinson, and John Trinder.Interaction of chemical and state effects on ventilation duringsleep onset. J. Appl. Physiol. 81(5):2235-2243, 1996.Ventilation varies as a function of state, beinghigher during wakefulness (as indicated by alpha electroencephalogramactivity) than during sleep (theta activity). A recent experimentobserved a progressive increase in the magnitude of these state-relatedfluctuations in ventilation over the sleep-onset period (28). The aimof the present experiment was to test the hypothesis that this effectresulted from chemical (feedback-related) amplification of stateeffects on ventilation. A hyperoxic condition was used to eliminateperipheral chemoreceptor activity. It was hypothesized that hyperoxiawould reduce the amplification of changes in ventilation associatedwith electroencephalogram state transitions. Ventilation was measuredover the sleep-onset period under both hyperoxic and normoxicconditions in 10 young healthy male subjects. Sleep onsets were dividedinto three phases. Phase 1 corresponded to presleep wakefulness; andphases 2 and 3 corresponded to early and late sleep onset,respectively. The magnitudes of state-related changes in ventilationduring phases 2 and 3, and under hyperoxic and normoxic conditions werecompared using a phase by condition analysis of variance. Resultsrevealed a significant phase by condition interaction, confirming that hyperoxia reduced the amplification of state-related changes in ventilation by selectively decreasing the magnitude of phase 3 statechanges in ventilation. However, some degree of amplification wasevident during hyperoxia, thus the results demonstrated that peripheralchemoreceptor activity contributed to the amplification ofstate-related changes in ventilation but that additional factors mayalso be involved.

     

Upper airway and respiratory muscle responses to continuous negative airway pressure

To determine upper airway and respiratory muscle responses to nasal continuous negative airway pressure (CNAP), we quantitated the changes in diaphragmatic and genioglossal electromyographic activity, inspiratory duration, tidal volume, minute ventilation, and end-expiratory lung volume (EEL) during CNAP in six normal subjects during wakefulness and five during sleep. During wakefulness, CNAP resulted in immediate increases in electromyographic diaphragmatic and genioglossal muscle activity, and inspiratory duration, preserved or increased tidal volume and minute ventilation, and decreased EEL. During non-rapid-eye-movement and rapid-eye-movement sleep, CNAP was associated with no immediate muscle or timing responses, incomplete or complete upper airway occlusion, and decreased EEL. Progressive diaphragmatic and genioglossal responses were observed during non-rapid-eye-movement sleep in association with arterial O2 desaturation, but airway patency was not reestablished until further increases occurred with arousal. These results indicate that normal subjects, while awake, can fully compensate for CNAP by increasing respiratory and upper airway muscle activities but are unable to do so during sleep in the absence of arousal. This sleep-induced failure of load compensation predisposes the airways to collapse under conditions which threaten airway patency during sleep. The abrupt electromyogram responses seen during wakefulness and arousal are indicative of the importance of state effects, whereas the gradual increases seen during sleep probably reflect responses to changing blood gas composition.     

State and chemical drive modulate respiratory variability.

The quantification of respiratory variability may provide insight into the integrative control of breathing. To test the hypothesis that sleep and/or increased chemical drive modifies respiratory variability, six male adult Sprague-Dawley rats were instrumented with diaphragm electromyographic (EMG) electrodes and exposed to 0, 2.5, and 5.0% CO2 with a balance of room air during wakefulness and behaviorally determined sleep. Respiratory interval (Ttot), peak diaphragm EMG, and ventilation index (peak diaphragm EMG/Ttot) were calculated for 1,024 sequential breaths. The variability of breathing was quantified with a measurement of signal complexity, the approximate entropy, and two autocorrelation measurements, the autoregressive power spectrum slope and the detrended fluctuation analysis slope. Elevated chemical drive and/or sleep significantly modulated the variability of ventilation index and Ttot. There were also significant interactions between state and CO2 drive in all respiratory parameters. We conclude that state (sleep or wakefulness) and increased chemical drive affect respiratory variability differentially.     

Occlusion pressure and ventilation during sleep in normal humans

Previous investigation in normal humans has demonstrated reduced ventilation and ventilatory responses to chemical stimuli during sleep. Most have interpreted this to be a product of decreasing central nervous system sensitivity to the normal stimuli that maintain ventilation, whereas other factors such as increasing airflow resistance could also contribute to this reduction in respiration. To improve our understanding of these events, we measured ventilation and occlusion pressures (P0.1) during unstimulated ventilation and rebreathing-induced hypercapnia during wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Eighteen subjects (10 males and 8 females) of whom seven were snorers (5 males and 2 females) were studied. Ventilation was reduced during both NREM and REM sleep (P less than 0.05), but this decrement in minute ventilation tended to be greater in snorers than nonsnorers. Unstimulated P0.1, on the other hand, was maintained or increased during sleep in all groups studied, with males and snorers showing the largest increase. The hypercapnic ventilatory response fell during both NREM and REM sleep and tended to be lower during REM than NREM sleep. However, the P0.1 response to hypercapnia during NREM sleep was well maintained at the waking level although the REM response was statistically reduced. These studies suggest that the mechanism of the reduction in ventilation and the hypercapnic ventilatory response seen during sleep, particularly NREM sleep, is likely to be multifactorial and not totally a product of decreasing central respiratory drive.     

Effects of selective sleep deprivation on ventilation during recovery sleep in normal humans.

To assess the effects of selective sleep loss on ventilation during recovery sleep, we deprived 10 healthy young adult humans of rapid-eye-movement (REM) sleep for 48 h and compared ventilation measured during the recovery night with that measured during the baseline night. At a later date we repeated the study using awakenings during non-rapid-eye-movement (NREM) sleep at the same frequency as in REM sleep deprivation. Neither intervention produced significant changes in average minute ventilation during presleep wakefulness, NREM sleep, or the first REM sleep period. By contrast, both interventions resulted in an increased frequency of breaths, in which ventilation was reduced below the range for tonic REM sleep, and in an increased number of longer episodes, in which ventilation was reduced during the first REM sleep period on the recovery night. The changes after REM sleep deprivation were largely due to an increase in the duration of the REM sleep period with an increase in the total phasic activity and, to a lesser extent, to changes in the relationship between ventilatory components and phasic eye movements. The changes in ventilation after partial NREM sleep deprivation were associated with more pronounced changes in the relationship between specific ventilatory components and eye movement density, whereas no change was observed in the composition of the first REM sleep period. These findings demonstrate that sleep deprivation leads to changes in ventilation during subsequent REM sleep.     

Postnatal maturation of ventilation and breathing pattern in kittens: influence of sleep

Ventilation and breathing pattern were studied in kittens at 1, 2, 3, 4, and 8 wk of life during quiet wakefulness (W), quiet sleep (QS), and active sleep (AS) with the barometric method. Tidal volume (VT), respiratory frequency (f), ventilation (VE), inspiratory time (TI), expiratory time (TE), mean inspiratory flow (VT/TI), and respiratory "duty cycle" (TI/TT) were measured. VT, VE, TI, TE, and VT/TI increased; f decreased and TI/TT remained constant during postnatal development in wakefulness and in both sleep states. No significant difference was observed between AS and QS for all the ventilatory parameters except TI/TT, which was greater in QS than in AS at 2 wk. VE was larger in W than in both AS and QS at all ages. This was mainly due to a greater f, TI/TT remaining constant. VT/TI, which represents an index of the central inspiratory activity, was larger in W than in sleep, VT not being significantly different whatever the stage of consciousness. The results of this study show that in the kitten 1) unlike in the adult cat, ventilation and breathing pattern are similar in QS and in AS; 2) in sleep, the central inspiratory drive appears to be independent of the type of sleep; and 3) in wakefulness, the increase of the central inspiratory activity could be related to important excitatory inputs.     

Activation of upper airway muscles before onset of inspiration in normal humans

Animal studies have shown activation of upper airway muscles prior to inspiratory efforts of the diaphragm. To investigate this sequence of activation in humans, we measured the electromyogram (EMG) of the alae nasi (AN) and compared the time of onset of EMG to the onset of inspiratory airflow, during wakefulness, stage II or III sleep (3 subj), and CO2-induced hyperpnea (6 subj). During wakefulness, the interval between AN EMG and airflow was 92 +/- 34 ms (mean +/- SE). At a CO2 level of greater than or equal to 43 Torr, the AN EMG to airflow was 316 +/- 38 ms (P < 0.001). During CO2-induced hyperpnea, the AN EMG to airflow interval and AN EMG magnitude increased in direct proportion to CO2 levels and minute ventilation. During stages II and III of sleep, the interval between AN EMG and airflow increased when compared to wakefulness (P < 0.005). We conclude that a sequence of inspiratory muscle activation is present in humans and is more apparent during sleep and during CO2-induced hyperpnea than during wakefulness.     

Sleep-induced periodic breathing and apnea: a theoretical study

To elucidate the mechanisms that lead to sleep-disordered breathing, we have developed a mathematical model that allows for dynamic interactions among the chemical control of respiration, changes in sleep-waking state, and changes in upper airway patency. The increase in steady-state arterial PCO2 accompanying sleep is shown to be inversely related to the ventilatory response to CO2. Chemical control of respiration becomes less stable during the light stage of sleep, despite a reduction in chemoresponsiveness, due to a concomitant increase in "plant gain" (i.e., responsiveness of blood gases to ventilatory changes). The withdrawal of the "wakefulness drive" during sleep onset represents a strong perturbation to respiratory control: higher magnitudes and rates of withdrawal of this drive favor instability. These results may account for the higher incidence of periodic breathing observed during light sleep and sleep onset. Periodic ventilation can also result from repetitive alternations between sleep onset and arousal. The potential for instability is further compounded if the possibility of upper airway occlusion is also included. In systems with high controller gains, instability is mediated primarily through chemoreflex overcompensation. However, in systems with depressed chemoresponsiveness, rapid sleep onset and large blood gas fluctuations trigger repetitive episodes of arousal and hyperpnea alternating with apneas that may or may not be obstructive. Between these extremes, more complex patterns can arise from the interaction between chemoreflex-mediated oscillations of shorter-cycle-duration (approximately 36 s) and longer-wavelength (approximately 60-80 s) state-driven oscillations.     

Identification of respiratory vagal feedback in awake normal subjects using pseudorandom unloading.

Evidence of the Hering-Breuer reflex has been found in humans during anesthesia and sleep but not during wakefulness. Cortical influences, present during wakefulness, may mask the effects of this reflex in awake humans. We hypothesized that, if lung volume were increased in awake subjects unaware of the stimulus, vagal feedback would modulate breathing on a breath-to-breath basis. To test this hypothesis, we employed proportional assist ventilation in a pseudorandom sequence to unload the respiratory system above and below the perceptual threshold in 17 normal subjects. Tidal volume, integrated respiratory muscle pressure per breath, and inspiratory time were recorded. Both sub- and suprathreshold stimulation evoked a significant increase in tidal volume and inspiratory flow rate, but a significant decrease in inspiratory time was present only during the application of a subthreshold stimulus. We conclude that vagal feedback modulates respiratory timing on a breath-by-breath basis in awake humans, as long as there is no awareness of the stimulus.     

Respiration During Sleep in Children

In 22 children (11 boys and 11 girls), aged 9 to 13 years, respiration was monitored during one night of sleep. No child had a significant history of breathing problems during sleep. Sleep was recorded using standard techniques (electroencephalography, electrooculography, electromyography), and respiration was measured with nasal thermistors and abdominal or thoracic strain gauges. Respiratory pauses (five seconds or longer) were determined for all sleep stages. Respiratory rate was scored only in the first and last sleep cycles and during ten waking minutes before sleep onset. Respiratory rate was significantly affected by wakefulness or stage of sleep: highest in wakefulness and stage 1, lowest in stage 2 of the last sleep cycle. Regularity of respiratory rate showed a similar effect. Variance of respiratory rate was significantly lower in girls than boys. Respiratory pauses during sleep were seen in every child, ranging from 3 to 40 pauses per night (average, 17.2 for boys and 18.0 for girls). Significantly greater numbers of pauses per minute were seen in stage 1 and rapid eye movement (REM) sleep than in stages 2, 3 and 4. The longest respiratory pause was 25 seconds. The conclusion is made that a small number of respiratory pauses during sleep are normal in children of this age.     

Effects of sleep pressure on endogenous cardiac autonomic activity and body temperature.

This study investigated the effects of variations in sleep pressure on cardiac autonomic activity and body temperature. In a counterbalanced design, 12 healthy, young subjects (6 men and 6 women) remained recumbent during 30 h of wakefulness (high sleep pressure) and 6 h of wakefulness (low sleep pressure). Both periods of wakefulness were immediately followed by a sleep opportunity, and the first 2 h of sleep were analyzed. During extended hours of wakefulness, a reduction in heart rate was mediated by a decline in cardiac sympathetic activity (measured via preejection period) and the maintenance of cardiac parasympathetic activity (measured via respiratory sinus arrhythmia). In subsequent high-pressure sleep, parasympathetic activity was amplified and sympathetic activity was negatively associated with electroencephalographic slow-wave activity. Sleep deprivation had no impact on foot temperature, but it did alter the pattern of change in core body temperature. A downregulation of cardiac autonomic activity during both extended hours of wakefulness and subsequent sleep may respectively provide "protection" and "recovery" from the temporal extension of cardiac demand.     

Multichannel EEG analysis of respiratory evoked-potential components during wakefulness and NREM sleep

Airway occlusion in awake humans producesa somatosensory evoked response called the respiratory-related evokedpotential (RREP). In the present study, 29 channel evoked-potentialrecordings were obtained from seven men who were exposed to 250-msinspiratory airway occlusions during wakefulness, stage 1, stage 2, andslow-wave sleep. The RREP recorded during wakefulness was similar toprevious reports, with the unique observation of an additionalshort-latency positive peak with a mean latency of 25 ms. Short-latencyRREP components were maintained in non-rapid-eye-movement (NREM) sleep. The clearly seen N₁ vertex andlate positive complex components during wakefulness were markedlyattenuated during NREM sleep, and two large negative components(N₃₀₀ andN₅₅₀) dominated the sleep RREP.These findings indicate the maintenance of central nervous systemmonitoring of respiratory afferent information during NREM sleep,presumably to facilitate protective arousal responses topathophysiological respiratory phenomena.

     

Transition from acute to chronic hypercapnia in patients with periodic breathing: predictions from a computer model.

Acute hypercapnia may develop during periodic breathing from an imbalance between abnormal ventilatory patterns during apnea and/or hypopnea and compensatory ventilatory response in the interevent periods. However, transition of this acute hypercapnia into chronic sustained hypercapnia during wakefulness remains unexplained. We hypothesized that respiratory-renal interactions would play a critical role in this transition. Because this transition cannot be readily addressed clinically, we modified a previously published model of whole-body CO2 kinetics by adding respiratory control and renal bicarbonate kinetics. We enforced a pattern of 8 h of periodic breathing (sleep) and 16 h of regular ventilation (wakefulness) repeated for 20 days. Interventions included varying the initial awake respiratory CO2 response and varying the rate of renal bicarbonate excretion within the physiological range. The results showed that acute hypercapnia during periodic breathing could transition into chronic sustained hypercapnia during wakefulness. Although acute hypercapnia could be attributed to periodic breathing alone, transition from acute to chronic hypercapnia required either slowing of renal bicarbonate kinetics, reduction of ventilatory CO2 responsiveness, or both. Thus the model showed that the interaction between the time constant for bicarbonate excretion and respiratory control results in both failure of bicarbonate concentration to fully normalize before the next period of sleep and persistence of hypercapnia through blunting of ventilatory drive. These respiratory-renal interactions create a cumulative effect over subsequent periods of sleep that eventually results in a self-perpetuating state of chronic hypercapnia.     

Vagal feedback in the entrainment of respiration to mechanical ventilation in sleeping humans.

We studied the capacity of four "normal" and six lung transplant subjects to entrain neural respiratory activity to mechanical ventilation. Two transplant subjects were studied during wakefulness and demonstrated entrainment indistinguishable from that of normal awake subjects. We studied four normal subjects and four lung transplant subjects during non-rapid eye movement (NREM) sleep. Normal subjects entrained to mechanical ventilation over a range of ventilator frequencies that were within +/-3-5 breaths of the spontaneous respiratory rate of each subject. After lung transplantation, during which the vagi were cut, subjects did demonstrate entrainment during NREM sleep; however, entrainment only occurred at ventilator frequencies at or above each subject's spontaneous respiratory rate, and entrainment was less effective. We conclude that there is no absolute requirement for vagal feedback to induce entrainment in subjects, which is in striking contrast to anesthetized animals in which vagotomy uniformly abolishes entrainment. On the other hand, vagal feedback clearly enhances the fidelity of entrainment and extends the range of mechanical frequencies over which entrainment can occur.     

Intramuscular and esophageal electrode recordings of posterior cricoarytenoid activity in normal subjects

Six normal human subjects were studied to compare intramuscular and esophageal electrode recordings of posterior cricoarytenoid (PCA) muscle activity. A new electromyographic technique was developed to implant hooked wire electrodes into the PCA via a nasopharyngoscope. The esophageal electrode was similar to that used by other investigators to record PCA activity (P. C. Kosch et al. J. Appl. Physiol. 64: 1968-1978, 1988). Simultaneous recordings from the intramuscular and esophageal electrodes were obtained during wakefulness and sleep. Changes in esophageal electrode activity were compared with changes in intramuscular electrode activity under four conditions: 1) voluntary maneuvers, 2) differences in state, 3) nasal airway occlusion during non-rapid-eye-movement sleep, and 4) spontaneous variations in respiratory efforts during non-rapid-eye-movement or rapid-eye-movement sleep. Although similar results were obtained from the esophageal and intramuscular electrodes, differences were present between the two recordings during both wakefulness and sleep. The esophageal electrode recorded activity from surrounding muscles during voluntary maneuvers, vocalization, and quiet breathing in wakefulness. Discrepancies between the two electrode recordings during sleep occurred under conditions of increased and decreased respiratory motor output. The data suggest that the esophageal electrode may not give an accurate assessment of PCA activity during many conditions in wakefulness and sleep.     

Prolongation of the laryngeal chemoreflex after inhibition of the rostral ventral medulla in piglets: a role in SIDS?

We tested the hypothesis that inhibition of neurons within the rostral ventral medulla (RVM) would prolong the laryngeal chemoreflex (LCR), a putative stimulus in the sudden infant death syndrome (SIDS). We studied the LCR in 19 piglets, age 3-16 days, by injecting 0.05 ml of saline or water into the larynx during wakefulness, non-rapid eye movement (NREM) sleep, and REM sleep, before and after 1 or 10 mM muscimol dialysis in the RVM. Muscimol prolonged the LCR (P < 0.05), and the prolongation was greater when the LCR was stimulated with water compared with saline (P < 0.02). The LCR was longer during NREM sleep than during wakefulness and longest during REM sleep (REM compared with wakefulness). Muscimol had no effect on the likelihood of arousal from sleep after LCR stimulation. We conclude that the RVM provides a tonic facilitatory drive to ventilation that limits the duration of the LCR, and loss of this drive may contribute to the SIDS when combined with stimuli that inhibit respiration.     

Activity of medullary respiratory neurons during ventilator-induced apnea in sleep and wakefulness

Mechanical ventilation of cats in sleep andwakefulness causes apnea, often within two to three cycles of theventilator. We recorded 137 medullary respiratory neurons in four adultcats during eupnea and during apnea caused by mechanical ventilation. We hypothesized that the residual activity of respiratory neurons during apnea might reveal its cause(s). The results showed that residual activity depended on 1) theamount of nonrespiratory inputs to the cell (cells with morenonrespiratory inputs had greater amounts of residual activity);2) the cell type (expiratory cellshad more residual activity than inspiratory cells); and 3) the state of consciousness (moreresidual activity in wakefulness and rapid-eye-movement sleep than innon-rapid-eye-movement sleep). None of the cells showed an activationduring ventilation that could explain the apnea. Residual activity ofapproximately one-half of the cells was modulated in phase with theventilator. The strength of this modulation was quantified by using aneffect-size statistic and was found to be weak. The patterns ofmodulation did not support the idea that mechanoreceptors excite somerespiratory cells that, in turn, inhibit others. Indeed, most cells,inspiratory and expiratory, discharged during the deflation-inflationtransition of ventilation. Residual activity failed to reveal the causeof apnea but showed that during apnea respiratory neurons act as ifthey were disinhibited and disfacilitated.