The effect of sleep deprivation on activity of the genioglossus muscle

Sleep deprivation appears to increase the severity of obstructive sleep apnea, and inadequate activation of the genioglossus muscle may play an important role in the pathogenesis of obstructive sleep apnea. Therefore, we investigated the effect of sleep deprivation on genioglossal electromyographic (EMG) activity. Eleven men were studied during room air breathing and CO2 rebreathing before sleep deprivation (control), after 1 night of sleep deprivation, and the day after sleep recovery. We measured inspired minute ventilation, tidal volume, respiratory frequency, and peak integrated inspiratory genioglossal EMG activity. After sleep deprivation, no significant changes in inspiratory minute ventilation or tidal volume occurred during room air breathing or CO2 rebreathing, but the breathing frequency during CO2 rebreathing increased significantly after sleep deprivation. Genioglossal EMG activity was diminished during CO2 rebreathing after sleep deprivation, but this was significant only in subjects 30 yr of age and older. The fall in EMG activity was independent of changes in tidal volume. All variables returned towards control levels after sleep recovery. We conclude that sleep deprivation selectively decreases genioglossal EMG activity during CO2 rebreathing in awake older subjects. This influence of sleep deprivation may play a role in the pathogenesis or severity of obstructive sleep apnea.     

Selective reduction of genioglossal muscle activity by alcohol in normal human subjects

We recorded ventilation and genioglossal electromyographic activity in 12 awake, normal subjects before and after they drank 1 ml of ethyl alcohol per kg of body weight. Measurements were made during quiet room air breathing and during hypercapnic rebreathing. Alcohol did not alter minute ventilation, the pattern of breathing, or the ventilatory response to CO2, but it significantly reduced genioglossal activity in both quiet breathing and hypercapnia. The effect was more consistent in male than in female subjects. These results indicate that the neural mechanisms underlying the respiratory activity of the genioglossus are more susceptible to depression by alcohol than those serving the muscles of the ventilatory pump. This susceptibility may be important in the exacerbation by alcohol of obstructive apnea during sleep.     

A model of the chemoreflex control of breathing in humans: model parameters measurement

We reviewed the ventilatory responses obtained from rebreathing experiments on a population of 22 subjects. Our aim was to derive parameter estimates for an 'average subject' so as to model the respiratory chemoreflex control system. The rebreathing technique used was modified to include a prior hyperventilation, so that rebreathing started at a hypocapnic P(CO2) and ended at a hypercapnic P(CO2). In addition, oxygen was added to the rebreathing bag in a controlled manner to maintain iso-oxia during rebreathing, which allowed determination of the response at several iso-oxic P(O2) levels. The breath-by-breath responses were analysed in terms of tidal volume, breathing frequency and ventilation. As P(CO2) rose, ventilation was first steady at a basal value, then increased as P(CO2) exceeded a breakpoint. We interpreted this first breakpoint as the threshold of the combined central and peripheral chemoreflex responses. Above, ventilation increased linearly with P(CO2), with tidal volume usually contributing more than frequency to the increase. When breathing was driven strongly, such as in hypoxia, a second breakpoint P(CO2) was often observed. Beyond the second breakpoint, ventilation continued to increase linearly with P(CO2) at a different slope, with frequency usually contributing more than tidal volume to the increase. We defined the parameters of the variation of tidal volume, frequency and ventilation with P(O2) and P(CO2) for an average subject based on a three-segment linear fit of the individual responses. These were incorporated into a model of the respiratory chemoreflex control system based on the general scheme of the 'Oxford' model. However, instead of considering ventilatory responses alone, the model also incorporates tidal volume and frequency responses.     

Effects of non-REM sleep upon respiratory drive and the respiratory pump in humans

We observed that ventilation fell and end-tidal CO2 rose in the change from wakefulness to non-REM (NREM) sleep in 4 normal human subjects studied on two nights each. We hypothesized that the observed ventilatory depression was due to effects of sleep both upon the central respiratory neural output and upon the mechanical respiratory pump. Both the central controller response to CO2, as measured by diaphragmatic and intercostal EMG activity, and the ability of the respiratory pump in effecting ventilation in response to diaphragmatic or intercostal activation, as measured by the relationship between the EMG activities and minute ventilation, are reduced in NREM sleep. We describe a general method of apportioning the separate effects of sleep, or other factors, upon the central respiratory controller, the respiratory mechanical pump, and the metabolic rate, in determining the total observed increase in end-tidal CO2.     

Low dose aminophylline selectively increases upper airway motor activity in normals

Because certain pharmacologic agents differentially influence upper airway and diaphragm motor activity, we postulated that the adenosine antagonist theophylline might preferentially increase alae nasi activity in human subjects. Using a double-blinded, randomized, placebo controlled design, we studied the effect of low dose aminophylline (1-2 mg/kg) on alae nasi and diaphragm surface electromyographic (EMG) activity. Seven healthy volunteers served as subjects for two trials on separate days. Subjects breathed from a close circuit while end tidal PCO2 was held constant in the eucapnic range. During each trial we recorded EMG signals from the alae nasi and diaphragm before and after intravenous infusion of either aminophylline or placebo. After the administration of aminophylline, the mean alae nasi EMG signal increased 87 +/- 31 (SD)% (P less than 0.005) while the mean diaphragmatic EMG signal did not change. There was no significant change in either the alae nasi or diaphragmatic EMG signal after placebo. There was no change in minute ventilation, tidal volume, or respiratory frequency after either aminophylline or placebo. We speculate that low dose aminophylline produces a selective increase in upper airway muscle activity through stimulation of the reticular activating system.     

Respiratory activity of genioglossus. Interaction between alcohol and the menstrual cycle

Alcohol consistently decreases genioglossal electromyographic (EMG) activity in awake men, but in women this response is more variable, possibly because of the menstrual cycle. To assess the interaction between alcohol and the menstrual cycle on genioglossal EMG activity, we measured ventilation and genioglossal EMG activity in 9 normal women before and after they drank 1 ml/kg alcohol. The effect of alcohol on ventilation and genioglossal EMG activity was studied twice in each subject: once during the follicular phase and again during the luteal phase of the menstrual cycle. Measurements were made while the subjects breathed room air and rebreathed a hypercapnic gas mixture. The ventilatory response to CO2 was significantly greater during the luteal phase of the menstrual cycle. Alcohol had no effect on resting ventilation or the ventilatory response to CO2 during either phase of the menstrual cycle. However, alcohol significantly decreased peak integrated genioglossal EMG activity during the follicular (low progesterone) phase but not during the luteal (high progesterone) phase of the cycle. The relative alcohol resistance of genioglossal EMG activity during the luteal phase may explain in part the low incidence of sleep-disordered breathing in premenopausal women and the benefit that some male patients with obstructive sleep apnea have derived from treatment with progesterone.     

Effects of volume and frequency of mechanical ventilation on respiratory activity in humans

This study evaluated the interaction between respiratory chemical drive and non-chemical factors related to the frequency and level of thoracic displacement during mechanical ventilation in shaping respiratory activity. Ten normal subjects were artificially hyperventilated with a positive-pressure mechanical respirator to a baseline end-tidal PCO2 of approximately 30 Torr. Thereafter, in separate trials, the end-tidal PCO2 was increased by (a) progressively raising the concentration of CO2 in the inspired gas (FICO2) while holding tidal volume (VT) and breathing frequency (f) constant, (b) lowering f while holding VT and FICO2 constant, and (c) lowering VT while maintaining a constant f and FICO2. Initially, as the PCO2 rose above baseline levels with increases in FICO2, there was no change in inspiratory muscle activity, as measured by the peak inspiratory airway pressure, until the PCO2 reached 40 Torr. This PCO2 threshold for a change in respiratory activity was significantly reduced when the tidal volume or frequency of mechanical ventilation was lowered. These results suggest that non-chemical drives related to the frequency and level of thoracic displacement interact with chemical stimuli in shaping respiratory activity.     

Ventilatory failure during resistive loaded breathing in the newborn primate

Previous investigations have shown that ventilatory failure during severe inspiratory resistive loading (IRL) in the 21-day-old infant primate occurs secondary to a decrease in respiratory frequency, that is, central failure. To examine the response of the more immature newborn to IRL, minute ventilation (V′_E), arterial blood gases and pH, minute diaphragmatic electromyogram (EMG) activity, peak inspiratory airway pressure, and the centroid frequency (Fc) of the diaphragmatic EMG power spectrum were measured in four unanesthetized tracheotomized 2-day-old monkeys during various levels of IRL, until either (1) ventilatory failure occurred (ventilatory failure run) or (2) normocapnia was sustained for 1 hr (successful trial). During successful trials, minute ventilation, breathing frequency, tidal volume, Fc, and P_aCO₂ were sustained at baseline levels and an increase in minute EMG activity and peak inspiratory airway pressure were observed. In contrast, during ventilatory failure runs, minute ventilation and tidal volume fell and P_aCO₂ rose compared to their respective baseline values. Respiratory frequency did not change. The decline in tidal volume occurred despite significant increases in minute diaphragmatic EMG activity and peak inspiratory airway pressure. No shifts in Fc were noted, suggesting that peripheral diaphragmatic fatigue did not occur. We conclude that ventilatory failure during IRL in the 2-day-old monkey is due to the animal's inability to defend tidal volume as opposed to central failure. Pediatr Pulmonol. 1998; 26:312–318. © 1998 Wiley-Liss, Inc.     

Ventilatory control after pulmonary resection

Because pulmonary resection decreases pulmonary compliance, the effects of resection on ventilation might be similar to the known effects of elastic loading. We evaluated the breathing pattern and ventilatory drive in 12 patients before and after pulmonary resection with mean tissue loss of 4 segments. During resting ventilation, the only significant change after resection was a decrease in inspiratory time (Tl). At a higher level of minute ventilation (VE), induced by CO2 rebreathing, significant changes included increased respiratory frequency, decreased tidal volume and Tl, and increased occlusion pressure (P0.1). Both ventilation and occlusion pressure responses to CO2 (delta VE/delta PACO2, delta P0.1/delta PACO2) were unchanged after resection. We conclude that increased ventilation induced by CO2 rebreathing unmasks a breathing pattern after pulmonary resection which is similar to that seen with breathing against an external elastic load.     

Postural effects on electromyographic activity of the transversus abdominis muscle]

During breathing at rest in humans, electromyographic activity of the expiratory muscles (EMGem), tidal volume (VT), and minute ventilation (V(I)) are higher when standing than when supine. EMGem is known to correlate with VT and V(I). It is not known whether increased EMGem when standing results directly from the change in posture or indirectly from postural changes in ventilatory pattern. Moving average electromyographic activity of the transversus abdominis (EMGta) was recorded using a pair of fine wire electrodes during carbon dioxide (CO2) rebreathing both while standing and while supine. At matched end-tidal CO2 (ETCO2), VT, or V(I) values, EMGta was significantly higher when standing than when supine. Postural differences in EMGta had no correlation with increasing ETCO2, VT, or V(I) during CO2 rebreathing. These results suggested that both the direct effect of the postural change and an indirect effect through changes in ventilatory pattern contribute to the increased EMGem observed when standing compared to that when supine.     

Influence of breathing frequency and tidal volume on cardiac output

The aim of our experiment was to investigate the influence of increasing either breathing frequency or tidal volume on cardiac output (Q), in normocapnia. We measured Q with a CO2 rebreathing method in 6 men and 6 women in the sitting and the supine position, imposing different breathing patterns: in one set of experiments tidal volume was kept constant at 1 L while breathing frequency was randomly changed between 20, 30 and 40 breaths/min; in another breathing frequency was kept constant at 30 breaths/min while tidal volume was randomly altered between 1, 1.5 and 2 L. Switching from open circuit breathing to rebreathing (for measurement of Q) required no change in breathing pattern. From the beginning, CO2 was added to the inspired gas to maintain end-tidal FCO2 at 0.054, so as to obtain steady state conditions throughout the measurements. Q rose significantly when tidal volume was increased (938 ml/L rise in tidal volume when sitting, and 743 ml/L when supine). Breathing frequency had an insignificant effect (213 ml/10 breaths frequency increase when sitting and 142 ml/10 breaths when supine). The greater influence of ventilation on Q when sitting than when supine is best explained by the fact that in the latter position venous return is already high. There are no demonstrable differences in this effect between males and females.     

Role of airway mechanoreceptors in the inhibition of inspiration during mechanical ventilation in humans

The purpose of this study was to demonstrate a neuromechanical inhibitory effect on respiratory muscle activity during mechanical ventilation and to determine whether upper and lower airway receptors provide this inhibitory feedback. Several protocols were completed during mechanical ventilation: (1) positive and negative pressure changes in the upper airway, (2) airway anesthesia to examine the consequences of receptor blockade on respiratory muscle activity, (3) increasing FRC with positive end-expiratory pressure to study the effect of hyperinflation or stretch on respiratory muscle activity, and (4) use of heart-lung transplant patients to determine the effects of vagal denervation on respiratory muscle activity. All subjects were mechanically hyperventilated with positive pressure until inspiratory muscle activity was undetectable and the end-tidal PCO2 decreased to less than 30 mm Hg. End-tidal PCO2 (PETCO2) was increased by either adding CO2 to the inspired gas or decreasing tidal volume (50 ml/min). The PETCO2 where a change in inspiratory muscle activity occurred was taken as the recruitment threshold (PCO2RT). Neuromechanical feedback caused significant inspiratory muscle inhibition during mechanical ventilation, as evidenced by the difference between PCO2RT and PETCO2 during spontaneous eupnea (45 +/- 4 versus 39 +/- 4 mm Hg) and a lower PCO2RT when tidal volume was reduced with a constant frequency and fraction of inspired CO2. Recruitment threshold was unchanged during positive and negative pressure ventilation, during upper and lower airway anesthesia, and in vagally denervated lung transplant patients. These findings demonstrate that neuromechanical feedback causes highly significant inhibition of inspiratory muscle activity during mechanical ventilation; upper and lower airway receptors do not appear to mediate this effect.     

Breathing pattern and neuromuscular drive during CO2 rebreathing in normal man and in patients with COPD

In 11 normal subjects and in 10 patients with chronic obstructive pulmonary disease we evaluated breathing pattern and mouth occlusion pressure (PO.1), while breathing room air and during reinhalation of a hypercapnic hyperoxic gas mixture. In the breathing pattern we analyzed the time and volume components of the respiratory cycle: tidal volume (VT), inspiratory time (Ti), expiratory time (Te), total time of respiratory cycle (Ttot); mean inspiratory flow (VT/Ti) and Ti/Ttot ratios, respiratory frequency (RF) and instantaneous ventilation (VE). In the normal subjects, increase in VE during rebreathing mainly depended on an increase in both VT and VT/Ti without significant changes in Ti. During CO2 rebreathing the patients exhibited a lesser increase in VE compared to normals, due to a lesser increase in VT. However, expressing VT in percent of resting inspiratory capacity showed that VT attained at the end of rebreathing (VTmax) was similar to that noted in the normal subjects at the same minute of rebreathing. Furthermore, percent increase in VE, VT, VT/Ti and PO.1 between resting value and that at 56 mm Hg (delta %), were significant in both groups with a major increase in the normal subjects for VE and VT/Ti. In comparison, delta % decreases in both Te and Ttot were found to be significant only in the normal subjects. VT/Ti was related to VE in a similar way in the two groups. In contrast, in the normal subjects, Ti/Ttot did not increase with increasing VE. During rebreathing increase in PO.1 was found to be similar in the normal subjects and in patients. However, for a given neuromuscular drive VE and VT/Ti were greater in the normal subjects than in the patients. These data show that in the patients as a whole no significant changes in breath intervals occur during CO2 rebreathing. Furthermore, in patients, in spite of a similar increase in neuromuscular drive, the efficiency by which inspiratory muscle output (PO.1) is converted into VT/Ti was found to be reduced.     

Awake inspiratory airway occlusion in normal humans is followed by hyperpnea and hypocapnia

The ventilatory response following 15 seconds of inspiratory airway occlusion at functional residual capacity (FRC) was studied in nine normal supine awake subjects. Expired minute ventilation (VE), CO2 output (VCO2), tidal volume (VT), and end-tidal PCO2 (PETCO2) were measured on a breath-by-breath basis. Alveolar PCO2 rose 5.6 mm Hg during the apnea (P less than 0.001). Ventilation rose 10.8 L/min on the first breath following apnea and remained elevated above control measurements for five breaths (P less than 0.05). The persistent hyperpnea was due to an increase in tidal volume and was associated with alveolar hypocapnia for 6 breaths or 30 sec (P less than 0.05) and an increase in CO2 output for 4 breaths (P less than 0.05). Changes in end-tidal PCO2 correlated with excess CO2 output relative to control measurements immediately prior to airway occlusion (P less than 0.03). After 15 sec airway occlusion at FRC, there is alveolar hypercapnia with a 2.6-fold first breath rise in ventilation. Persistent alveolar hyperventilation lasting 30 sec following airway occlusion may be due to delays in central chemoreceptor response or an afterdischarge phenomenon. This overshoot hypercapnia following airway occlusion may have some relevance to the development of central apneas following obstructive apnea episodes.     

Developmental changes in the ventilatory response of the newborn to added airway resistance

Postnatal development of the steady-state response to inspiratory resistive loading was studied in eight 48-hour-old and seven 24-day-old tracheostomized monkeys. The newborn subjects did not maintain minute ventilation (Vl) with increasing loads of from 2 to 6 times baseline respiratory resistance, whereas the older subjects kept Vl constant when challenged by the same added resistances. The response patterns in both groups were characterized by a prolongation of Tl and Tl/Ttot, a reduction of respiratory frequency, and increases in airway occlusion pressure and respiratory work output. Apart from Vl, tidal volume (VT) was the only other ventilatory variable that differed significantly between age groups during loading. Arterial CO2 and O2 did not change from baseline in either group during loading, indicating that both age groups defended blood gas values equally well. The increases in occlusion pressures, inspiratory work output, and the maintenance of PaCO2 in the newborns indicated the presence of load compensatory mechanisms despite the fact that Vl was not strictly defended.     

Cardiorespiratory responses to sudden release of circulatory occlusion during exercise

Cardiovascular and respiratory parameters were measured during and after release of pressure in thigh cuffs which occluded circulation to the legs of four human subjects exercising on a bicycle ergometer. The subjects exercised at 200 kg/min while thigh cuffs were inflated for 4 min and then released. Responses from 6 to 8 identical experiments were ensemble averaged so the precise timing of delays could be obtained. Five to ten seconds following cuff release, end-tidal CO2 increased, marking arrival of the trapped blood at the lungs. Ten to eighteen seconds after this increase in end-tidal CO2, ventilation, respiratory rate and tidal volume increased. This delay in ventilation must have resulted in an increase in arterial PCO2 and suggests that arterial chemoreceptors mediated the responses, and that no venous chemoreceptors or CO2-flux or disequilibrium receptors in the lung need be postulated.     

Ventilatory and waking responses to CO2 in sleeping dogs.

We examined ventilatory and waking responses to hyperoxic hypercapnia in 3 dogs during natural sleep. Progressive hypercapnia was induced by a rebreathing technique, and sleep was determined by electroencephalographic and behavioral criteria. In non-rapid eye movement sleep (high-voltage, slow-frequency electroencephalography) rebreathing continued for 0.99 +/- 0.05 min (mean +/- SE) before arousal occurred, and the alveolar PCO2, at arousal was 54.2 +/- 3.4 mm Hg. In contrast, during rapid eye movement sleep, rebreathing lasted for 1.71 +/- 0.27 min (P less than 0.05) before arousal occurred and the alveolar PCO2 at arousal was 60.3 +/- 4.2 mm Hg (P less than 0.05). Linear regression analysis of breath-by-breath instantaneous minute volume of ventilation, tidal volume, and respiratory frequency against alveolar PCO2 revealed regression coefficients in rapid eye movements sleep that were 14 to 33 per cent of those found in non-rapid eye movement sleep, and correlation coefficients of 0.26 to 0.46, compared to 0.71 to 0.91 in non-rapid eye movement sleep. Thus, the link between CO2 and ventilation appeared to be strong in non-rapid eye movement sleep but considerably disrupted during rapid eye movement sleep. We conclude that centers involved in both waking and ventilatory responses to hypercapnia behave as if they are less aware of or responsive to CO2 in rapid eye movement sleep than in non-rapid eye movement sleep.     

Respiratory responses of piglets to hypercapnia during postnatal development: effects of opioids.

Resting respiratory and cardiovascular functions and the response to CO2 rebreathing were compared between 2.5 +/- 0.7 (mean +/- SE) and 34.1 +/- 1.9 day old piglets, before and after the opioid antagonist naltrexone (1 mg/kg IV). At rest, tidal volume, both absolute and per m2, inspiratory and expiratory time, absolute minute ventilation, and mean arterial pressure increased with age, and breathing frequency, minute ventilation per m2, and heart rate decreased, all of these with as well as without naltrexone. During hypercapnia, the pattern, but not the quantitative aspects of breathing changed with age. At rest, naltrexone produced hyperventilation in the young, but not in the older group. During hypercapnia, naltrexone had a sparse effect in both ages. We conclude that, in the anesthetized piglet, ventilatory functions at rest undergo change with postnatal age, but breathing responses to hypercapnia exhibit maturation in pattern only and not in magnitude. Whereas resting ventilation of young piglets is modulated by endogenous opioids, hypercapnia may activate opioids to a limited extent and in a manner unrelated to age.     

Effects of chemical feedback on respiratory motor and ventilatory output during different modes of assisted mechanical ventilation.

The purpose of the study was to examine the effects of chemical feedback on respiratory motor and ventilatory output in conscious subjects ventilated on various modes of assisted mechanical ventilation. Seven subjects were connected to a ventilator and randomly ventilated on assist-volume control (AVC), pressure support (PS) or proportional assist ventilation (PAV). On each mode, the assist level was set to the highest comfortable level. Airway and oesophageal (Poes) pressures, tidal volume, respiratory frequency (fR) and end-tidal carbon dioxide tension (PET,CO2) were measured breath-by-breath. When the subjects were stable on each mode, the fraction of inspired carbon dioxide (FI,CO2) was increased stepwise, and changes in minute ventilation (V'E) and respiratory motor output, estimated by the pressure-time product of all the respiratory muscles per breath (PTPrm) and per minute (PTPminute), were observed. At zero FI,CO2, PTPminute/PET,CO2 did not differ between modes, while V'E/ PTPminute was significantly lower with PAV than that with PS and AVC. As a result V'E/PET,CO2 was significantly lower with PAV, preventing, unlike AVC and PS, a significant drop in PET,CO2. With PAV, independent of CO2, V'E/PTPminute remained constant, while it decreased significantly with increasing CO2 stimulus with PS and AVC. At high PET,CO2 respiratory effort was significantly lower with PAV than that with PS and AVC. In conclusion, the mode of mechanical ventilation modifies the effects of chemical feedback on respiratory motor and ventilatory output. At all carbon dioxide stimulus levels neuroventilatory coupling was better preserved with proportional assist ventilation than with pressure support and assist-volume control ventilation.     

Distribution of motor activity to expiratory muscles during sciatic nerve stimulation in the dog

The present study examined the effect of increasing sensory input from the lower limbs (assessed from the response to electrical stimulation of the sciatic nerve) on the distribution of electrical activity to the expiratory muscles. Expiratory muscle response to sciatic nerve stimulation (SNS) was compared to the response of the inspiratory muscles, and to their response to hypercapnia. In 16 anesthetized dogs afferent SNS increased ventilation and augmented the integrated EMG of all six expiratory muscles studied. Increases in abdominal muscle electrical activity were not uniform, being greater in the transversus abdominis and external oblique as compared to the internal oblique and the rectus abdominis. Increases in thoracic expiratory and inspiratory muscle activity during SNS were similar in magnitude. SNS performed while dogs were breathing 7% CO2, produced increased neural activity similar to those observed during O2 breathing. During CO2 rebreathing, at equal levels of minute ventilation, expiratory muscle responses to SNS and to CO2 were similar. In contrast, the rate of rise of the inspiratory muscle EMGs was greater during SNS. The present study indicates that the abdominal muscles participate in the respiratory response to afferent neural drive from skeletal muscles. The magnitude of their response is independent of their pre-stimulation level of activity and is similar to that observed during CO2 stimulated breathing.