The role of central chemosensitivity in central apnea of heart failure.
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Adult↗
Biomedical subjects
M Berthon-Jones
Publications and source records attributed to M Berthon-Jones.
Ventilatory response to oxygen after eucapnic hypoxia in conscious dogs.
In humans the ventilatory [minute ventilation (VI)] response to sustained hypoxia is biphasic: an initial brisk increase followed by a decline is usually seen. However, in adult dogs, the ventilatory response to a similar stimulus shows no decline. To evaluate if central ventilatory drive is altered by sustained hypoxia, we measured the lowest ventilation (nadir) as the lowest moving average of seven sequential breaths within 200 s after transition to hyperoxia (100% O2) after 3 different exposures: room air, 4-min (brief) eucapnic hypoxia (arterial O2 saturation = approximately 80%), and 12-min (prolonged) eucapnic hypoxia. The nadir hyperoxic VI after brief hypoxia (2.7 +/- 0.2 l/min) was similar to that after room air (2.6 +/- 0.2 l/min; P > 0.05), with both less than prior room air mean VI (P < 0.05). The nadir after prolonged hypoxia (3.5 +/- 0.3 l/min) was significantly greater than that after brief hypoxia (P < 0.05). This suggests that central ventilatory drive increases in conscious dogs after sustained eucapnic hypoxia. The reason for the difference in central ventilatory response to hypoxia between conscious dogs and adult humans is unexplained.
Animals↗
Breathing route and resistive loading: influence on ventilatory response to hypoxia in conscious dogs.
Unlike normal humans, the tracheostomized conscious dog does not show ventilatory adaptation in response to sustained isocapnic hypoxia. To determine whether this phenomenon is a result of the breathing route or the relatively low airflow resistance of tracheostomy breathing, we evaluated the ventilatory response to sustained isocapnic hypoxia (20 min; arterial oxyhemoglobin saturation = 80%) in five awake dogs during nasal-oral (mask) breathing, tracheal breathing, and tracheal breathing with added matched resistance of upper airway breathing. Mask breathing, like unloaded tracheal breathing, was associated with a consistent level of hyperventilation during the entire hypoxic exposure period. However, mask breathing was always less (P < 0.05) than that found during unloaded tracheal breathing. Loaded tracheal breathing during hypoxia resulted in initial hyperventilation similar to that of unloaded tracheal breathing followed by a "roll off" to a lower minute ventilation similar to that of mask breathing. Our findings demonstrate that ventilatory adaptation is only present during loaded tracheal breathing in dogs and suggest that the breathing route and upper airway resistive loading may play roles in ventilatory adaptation.
Airway Resistance↗
Ventilatory response to sustained eucapnic hypoxia in the adult conscious dog.
The ventilatory response to 20 min sustained isocapnic hypoxia (SaO2, 80 +/- 2%) was examined in 5 trained unanesthetized adult dogs breathing through an endotracheal tube. End tidal PCO2 was maintained at the resting levels. The dogs' conscious status was monitored by recording EEG and EOG on a chart recorder. The room temperature was kept between 19 and 21 degrees C. All tests were repeated in each dog on 2 occasions: (1) unloaded tracheal breathing or (2) resistive loaded breathing. During unloaded tracheal breathing, the average ventilation in response to sustained hypoxia rose from a control of 5.1 +/- 0.3 L/min (mean +/- within-dog SE) to 19.2 +/- 1.1 L/min at the initial stage of hypoxia. Ventilation remained at 20.7 +/- 1.3 L/min at 10 min, and then 19.7 +/- 1.4 L/min at the completion of the 20 min hypoxic exposure. There was no ventilatory adaptation observed (P greater than 0.05). After release from hypoxia, the ventilation fell abruptly to 7.6 +/- 0.8 L/min, which was higher than the resting baseline level (P less than 0.05), and then gradually returned to the resting baseline within 10 min. Experiments exposing the dogs to 40 min sustained hypoxia also failed to elicit significant adaptation. During resistive loading, the pattern of average ventilation in response to sustained hypoxia was similar to that observed in unloaded breathing tests. But the ventilatory recovery was longer than unloaded breathing, returning to the resting baseline within 20 min. Again, there was no ventilatory adaptation observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Adaptation, Physiological↗
Increased normoxic ventilation induced by repetitive hypoxia in conscious dogs.
To determine if a long-lasting increase in normoxic ventilatory drive is induced in conscious animals by repetitive hypoxia, we examined the normoxic [arterial O2 saturation (SaO2) > 93%] ventilatory response following successive episodes of 2-min eucapnic hypoxic challenges (SaO2 = 80%) in awake tracheotomized dogs. End-tidal CO2 was maintained at the resting level during and after repetitive hypoxia. The experimental protocol was performed twice in each of five dogs on separate days. To determine if changes in normoxic ventilation occurred between episodes of repetitive hypoxia, data were compared from six periods (epochs) for all experiments. The mean minute ventilation (VI) during three normoxic periods between episodes of intermittent hypoxia was 135, 154, and 169% of control (P < 0.05). VI during a 30-min recovery period was still higher at 183 and 172% of control (P < 0.05). Normoxic VI between hypoxic and recovery periods was significantly higher than the corresponding values in sham experiments. Our results indicate that a long-lasting increase in normoxic ventilation can be evoked in an awake unanesthetized dog by a short exposure to repetitive hypoxia.
Animals↗
Androgen blockade does not affect sleep-disordered breathing or chemosensitivity in men with obstructive sleep apnea.
As sleep apnea is more prevalent in men and testosterone has known effects on sleep apnea and chemosensitivity, reduction of androgen activity may influence sleep-disordered breathing and respiratory control. We studied the effect of 1 wk of treatment with flutamide, a nonsteroidal antiandrogen, on sleep, respiration, and ventilatory control in eight men with sleep apnea. Results on flutamide were compared with two baseline studies performed before and after the drug treatment period. Although effective androgen blockade was achieved as evidenced by increased hormone levels, flutamide had no effect on sleep architecture or chemoresponsiveness to hypoxia and hypercapnia. There was a trend towards a reduction in respiratory disturbance index in both NREM and REM sleep (41 +/- 4 baseline versus 34 +/- 3 flutamide, p = 0.09 NREM; 53 +/- 4 baseline versus 48 +/- 3 flutamide, p = 0.16 REM), but this was not significant. Our results indicate that androgen blockade had no clinically significant effect on sleep, sleep-disordered breathing, or chemosensitivity in patients with moderate to severe sleep apnea. More specific blockers such as gonadotrophin-releasing hormone analogs may have more clinical effect or, alternatively, androgen blockade may be more beneficial in patients with milder sleep apnea.
Adult↗
Erythropoietin concentrations in obstructive sleep apnoea.
Eight patients with obstructive sleep apnoea and a normal haemoglobin concentration underwent nocturnal studies during which oxyhaemoglobin saturation was recorded continuously with an ear oximeter and serum erythropoietin concentration was measured hourly by means of a radioimmunoassay. Serum erythropoietin concentrations remained within the normal range throughout the study despite falls in oxyhaemaglobin saturation in individuals to 33-78%. There was no relation between the degree of nocturnal hypoxaemia and serum erythropoietin concentrations. The brief cyclical episodes of hypoxaemia typical of obstructive sleep apnoea may not be a sufficient stimulus for erythropoietin secretion.
Adult↗
Effects of upper airway pressure on abdominal muscle activity in conscious dogs.
We have examined arousal and abdominal muscle electromyogram (EMGabd) responses to upper airway pressure stimuli during physiological sleep in four dogs with permanent side-hole tracheal stomata. The dogs were trained to sleep with a tightly fitting snout mask, hermetically sealed in place, while breathing through a cuffed endotracheal tube inserted through the tracheostomy. Sleep stage was determined by behavioral and electroencephalographic criteria. EMGabd activity was measured using bipolar fine-wire electrodes inserted into the abdominal muscle layers. Static increases or decreases in upper airway pressure (+/- 6 cmH2O), when applied at the snout mask or larynx (upper trachea), caused an immediate decrease in EMGabd on the first two to three breaths; EMGabd usually returned to control levels within the 1-min test interval. In contrast, oscillatory pressure waves at 30 Hz and +/- 3 cmH2O amplitude (or -2 to -8 cmH2O amplitude) produced an immediate and sustained reduction in IMGabd in all sleep states. Inhibition of EMGabd could be maintained over many minutes when the oscillatory pressure stimulus was pulsed by using a cycle of 0.5 s on and 0.5 s off. Oscillatory upper airway pressures were also found to be powerful arousal-promoting stimuli, producing arousal in 94% of tests in drowsiness and 66% of tests in slowwave sleep. The results demonstrate the presence of breath-by-breath upper airway control of abdominal muscle activity.
Abdomen↗
Abdominal muscle activity in conscious dogs: effect of sleep and route of breathing.
Abdominal muscle activity (EMGabd) was studied in 4 adult dogs during wakefulness and sleep. The dogs were previously prepared with a permanent side-hole tracheal stoma, and were trained to sleep with a tightly-fitted snout mask, hermetically sealed in place. They breathed either through a cuffed endotracheal tube inserted distally into the tracheal stoma (tracheal), or through the upper airway, with the tracheal stoma plugged (nasal). Sleep state was determined by behavioural, electroencephalographic and electromyographic criteria. EMGabd activity was measured using fine bipolar needles inserted into the abdominal muscle layers. Expiratory EMGabd augmented progressively from sleep onset to SWS regardless of route of breathing, and without major changes in the animal's ventilation. Maximal EMGabd occurred in SWS during nasal breathing; EMGabd increased from a mean of 16.6 +/- 0.3 mV awake, to 23.8 +/- 0.3 mV in SWS, representing an overall increase of 55.0 +/- 7.5% from the awake level. EMGabd increased similarly during tracheal breathing, with an overall increase of 62.0 +/- 15.4% in SWS. We conclude that the consistent augmentation of expiratory EMGabd activity in sleep indicates that expiration in the dog is an active process, which is enhanced during nasal breathing and NREM sleep.
Abdomen↗
Tracheal smooth muscle responses to upper airway pressure in conscious dogs.
We studied the influence of changes in pressure applied to the isolated upper airway of four conscious dogs on tracheal smooth muscle tone and breathing pattern. The dogs were prepared with a permanent side-hole tracheal stoma and were trained to sleep with a snout mask hermetically sealed in place while breathing through a cuffed endotracheal tube inserted distally into the tracheal stoma. Changes in tracheal smooth muscle tone were continuously monitored by measuring the pressure in the water-filled cuff that distended the tracheal airway while pressure changes were introduced in the upper airway independently of breathing. Increases or decreases of upper airway pressure (+/- 10 cmH2O) had little effect on tracheal airway smooth muscle tone. In contrast, an oscillating pressure wave at 30 Hz and +/- 3 cmH2O amplitude (or -3 to -7 cmH2O amplitude) caused a marked increase in tracheal airway smooth muscle tone. An elevated tracheal airway tone could be maintained over many minutes when the oscillating pressure stimulus was pulsed so that there was a cycle of 0.5 s on, 0.5 s off. This stimulus did not change the functional residual capacity but resulted in coughing, swallowing, or sighing in 54% of the tests. In the remaining tests, the pressure stimulus produced a rapid, shallow, and erratic breathing pattern. The tracheal airway constrictor response (but not the ventilatory response) was completely abolished by intravenous atropine. We suggest that upper airway vibration is a potentially powerful mechanism of reflex airway smooth muscle constriction.
Animals↗
Waking and genioglossus muscle responses to upper airway pressure oscillation in sleeping dogs.
We studied waking and genioglossus electromyographic (EMGgg) responses to oscillating pressure waves applied to the upper airways of three sleeping dogs. The dogs were previously prepared with a permanent side-hole tracheal stoma and were trained to sleep with a tight-fitting snout mask, hermetically sealed in place, while breathing through a cuffed endotracheal tube inserted through the tracheostomy. Sleep state was determined by behavioral, electroencephalographic, and electromyographic criteria, and EMGgg activity was measured using fine bipolar electrodes inserted directly into the muscle. Oscillatory pressure waves of 30 Hz and +/- 3 cmH2O (tested at atmospheric and subatmospheric upper airway pressures) were applied at the dog's nostrils or larynx, either constantly for a period of 1 min or in 0.5-s bursts. We found that the pressure stimulus had two major effects. First, it was a potentially powerful arousal-promoting stimulus. Arousal occurred in 78% of tests in slow-wave sleep (SWS) and 55% of tests in rapid-eye-movement (REM) sleep, with swallowing and sighing accompanying many of the arousals. Second, it produced an immediate and sustained augmentation of EMGgg, in wakefulness, SWS, and REM sleep. We conclude that oscillatory pressure waves in the upper airway, as found in snoring, produce reflex responses that help maintain upper airway patency during sleep. Loss of this type of reflex might contribute to the onset of obstructive sleep apnea in chronic snorers.
Anesthesia↗
Time course of change in ventilatory response to CO2 with long-term CPAP therapy for obstructive sleep apnea.
Nineteen subjects with the obstructive sleep apnea syndrome (10 with daytime arterial CO2 tension 44 mm Hg or higher) were treated with long-term nocturnal continuous positive airway pressure. The ventilatory response to CO2 (Read's method) was measured in triplicate prior to treatment and after 1, 2, 3, 7, and 14 or more nights of therapy. Seven subjects were tested on at least 4 occasions. For each test, slope of the response line and position of the response line (ventilation at a PCO2 of 60 mm Hg) were calculated. The subjects with initial high daytime CO2 showed no change in slope of response with treatment but showed a progressive increase in ventilation at any given degree of PCO2. Ventilation at a PCO2 of 60 mm Hg increased from a mean of 20.0 +/- 1.3 SEM L/min by 8.0 +/- 2.5 SEM L/min after 2 nights of therapy (p less than 0.05, two-way analysis of variance), and by 16.2 +/- 1.9 L/min after 2 wk or more (p less than 0.01). On average, there was no significant change in either slope or position of response in the subjects with initially normal daytime PCO2. We conclude that airway obstruction in sleep (in obstructive sleep apnea syndrome) leads in some subjects to respiratory failure in the daytime, with a left shift in the ventilatory response to CO2, and that this changes is usually reversible during the next several days.
Blood Gas Analysis↗
Ventilation and arousal responses to hypercapnia in normal sleeping humans.
We measured arousal and ventilatory responses to rebreathing from a small bag, initially approximately 7% CO2 in 40% O2, via a nose mask in 13 normal human adults. With deepening non-rapid-eye-movement sleep (NREM), males aroused at increasing alveolar PCO2 (mean +/- SE: stage II 58.6 +/- 1.7, stage III 61.2 +/- 1.0, stage IV 63.8 +/- 0.8 Torr), whereas in rapid-eye-movement sleep (REM), arousal alveolar PCO2 was 57.7 +/- 0.7 Torr, i.e., much lower than in stage III and IV NREM. Females showed no significant change in arousal alveolar PCO2, (II 57.6 +/- 0.9, III 57.3 +/- 1.3, IV 59.4 +/- 0.9, REM 56.3 +/- 1.0 Torr). Male ventilatory response was 2.5 +/- 0.1 (SE) 1 X min-1 X Torr-1 and fell by 49% in NREM (1.29 +/- 0.13) and by 69% in REM (0.78 +/- 0.18). Female response was little affected by state, being similar to male NREM response (wake 1.39 +/- 0.14, NREM 1.40 +/- 0.13, REM 1.11 +/- 0.26 1 X min-1 X Torr-1). In NREM tests, there was no change in sleep state until arousal, whereas in REM, subjects awoke abruptly with the onset of rebreathing (11 cases), showed a transient arousal with onset but continued in REM until final arousal (21 cases), or changed to NREM at onset (2 cases). These arousal results contrast sharply with findings in tracheostomized dogs and in obstructive sleep apnea syndrome, where asphyxic arousal is later in REM than in NREM, suggesting that the events at test onset in REM in the present study may be related to upper airway sensitivity to CO2 specific to REM.
Adult↗
Studies of oxygenation during sleep in patients with interstitial lung disease.
The pattern of change in arterial oxyhemoglobin saturation (SaO2%) during sleep was characterized in 13 patients with interstitial lung disease (ILD), 12 of whom had restrictive ventilatory impairment. Four patients snored during sleep. During the studies, 9 patients had unequivocal rapid eye movement (REM) sleep episodes. The total duration of each patient's REM episodes averaged 49 min (range, 26 to 93 min), which was 22 +/- 7% (1SD) of the total sleep duration. Seven of these 9 patients were nonsnorers but had definite falls in SaO2% during REM sleep (mean fall in SaO2%, 8 +/- 3%), and in 6 of them the falls in SaO2% were transient, with a mean duration of 28 +/- 12 s and a total duration of 6.4 +/- 3.9 min or 16 +/- 12% of the total REM sleep duration. The other nonsnorer showed sustained desaturation (SaO2, 80 to 85%) for his entire REM sleep period of 26 min. In the nonsnoring patients, the falls in SaO2% during REM sleep (8 +/- 3%) were usually greater than those occurring during awake exercise (6 +/- 7%). Two snorers had unexpected sleep apnea syndrome (minimal SaO2% during NREM sleep, 83 and 77%, respectively; minimal SaO2% during REM sleep, 58 and 67%, respectively). The other snorers had greater than 10% falls in SaO2% during NREM sleep. The breathing frequency in NREM sleep in patients with ILD (mean, 23 +/- 5 breaths/min) was persistently above the normal range (mean, 15 +/- 0.4 breaths/min). The possibility of sleep hypoxemia should be considered in the management of patients with ILD.
Adult↗
Nocturnal nasal-airway pressure for sleep apnea.
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Humans↗
Remission of severe obesity-hypoventilation syndrome after short-term treatment during sleep with nasal continuous positive airway pressure.
Two patients with the Pickwickian syndrome and with life-threatening sleep hypoxemia were treated with continuous positive airway pressure (CPAP) applied through the nares only during sleep periods. Each patient presented with severe daytime somnolence, disturbed sleep, nocturnal confusion, and daytime awake cardiorespiratory failure (PaCO2, 63 and 55 mmHg). Both patients demonstrated grossly abnormal breathing during sleep with severe sleep hypoxemia, the arterial oxyhemoglobin saturation (SaO2%) falling repetitively to levels below 50%. One patient had a hypoxemic convulsion during the initial sleep evaluation. Low levels (3.5 and 8.0 cm H2O) of continuous positive airway pressure, when applied via a comfortable nose mask, prevented occlusive apnea and obstructive hypopnea during sleep in both patients and maintained steady levels of arterial oxyhemoglobin saturation. There was rapid recovery of mental function and loss of cardiorespiratory failure within 3 days of treatment. After short-term treatment with nocturnal CPAP therapy (23 days and 35 days) both patients were able to sleep, unaided, without sleep-induced upper airway occlusion with arterial oxyhemoglobin levels sustained above 80%. We conclude that nasal CPAP therapy during sleep is an effective noninvasive therapy for patients with the Pickwickian syndrome, and may lead to a stable remission of the underlying severe disordered breathing in sleep.
Aged↗
Ventilatory and arousal responses to hypoxia in sleeping humans.
We measured ventilatory and arousal responses to progressive eucapnic hypoxia during wakefulness, nonrapid-eye-movement (NREM) sleep, and rapid-eye-movement (REM) sleep using a progressive isocapnic rebreathing method. Nine healthy adults (4 female, 5 male) slept with a mask glued to the face with medical silicone rubber and breathed from a closed valveless biased flow circuit, including an in-line bag-in-box and a variable soda-lime absorber. Progressive hypoxia was induced by consumption of oxygen and by gradual replacement of circuit volume with nitrogen. Tidal volume was measured by electrical integration of the flow signal from a pneumotach on the box. Arterial hemoglobin oxygen saturation (SaO2) was measured with an ear oximeter and end-tidal CO2 tension (PetCO2) was measured continuously and kept constant by variable absorption. Sleep state was identified using standard criteria with 2 channels each of EEG, submental EMG, and EOG. There was marked variability in arousal level both in NREM and REM sleep, with subjects failing to awaken by 70% SaO2, our previously agreed safety limit, on 12 of 26 NREM tests, and 7 of 15 REM tests. During wakefulness, the mean slope +/- SEM of the ventilatory response to hypoxia was 0.68 +/- 0.07 L/min% SaO2 (n = 36, mean PetCO2 = 37.0 mmHg). In NREM sleep, this response decreased to a mean of 0.42 +/- 0.06 L/min/% SaO2 (n = 26, mean PetCO2 = 37.2 mmHg). In REM sleep, the average ventilatory response was further decreased to 0.33 +/- 0.06 L/min/% SaO2 (n = 15, mean PetCO2 = 37.8 mmHg). Analysis of variance showed a significant state-dependent effect on ventilatory response (p less than 0.01). The wake-NREM and wake-REM differences were significantly different (p less than 0.05), but the NREM-REM difference was not (p greater than 0.2). In REM sleep, breath-to-breath variability was marked, and in 2 cases, the response was not significantly different from zero. In all 3 states, the entire ventilatory response was due to increments in tidal volume. We conclude that (1) at normal alveolar CO2 tension, hypoxia is a poor arousal stimulus in humans, both in NREM and REM sleep, and (2) the eucapnic hypoxic response is reduced but present in NREM sleep and similarly reduced but not always present in REM sleep.
Adult↗
Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares.
Five patients with severe obstructive sleep apnoea were treated with continuous positive airway pressure (CPAP) applied via a comfortable nose mask through the nares. Low levels of pressure (range 4.5-10 cm H2O) completely prevented upper airway occlusion during sleep in each patient and allowed an entire night of uninterrupted sleep. Continuous positive airway pressure applied in this manner provides a pneumatic splint for the nasopharyngeal airway and is a safe, simple treatment for the obstructive sleep apnoea syndrome.
Adolescent↗