Role of metabolic CO2 production in ventilatory response to steady-state exercise.

We examined the role of metabolic CO2 production in the hyperpnea of muscular exercise by comparing the response of alveolar ventilation to moderate levels of exercise with the response to venous infusion of CO2 at rest. Studies were performed in four awake sheep that were trained to run on a treadmill. The sheep had been cannulated for veno-venous extracorporeal perfusion so that CO2 could be infused into the peripheral venous blood through membrane lungs in the perfusion circuit. The sheep breathed room air through an endo-tracheal tube inserted through a tracheostomy, and samples of expired gas were collected for measurement of the rates of CO2 production and O2 consumption. All measurements were made in the steady state. In each of the four sheep, the relationship between alveolar ventilation and the rate of CO2 production could be described by a single linear function (r greater than 0.99; P less than 0.001), regardless of whether CO2 production was increased by exercise, venous CO2 infusion, or combinations of both procedures. This relationship applied for values of CO2 production up to 350% of control. In contrast, no unique relationship was found between the rate of alveolar ventilation and either the rate of O2 consumption, cardiac output, or mixed venous blood gas pressures. The findings indicate that the hyperpnea of mild to moderate steady-state exercise can be attributed to the associated increase in the rate of CO2 production. Therefore, there is no need to invoke obligatory nonmetabolic stimuli to account for the ventilatory response to steady-state exercise.

Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model.

Several epidemiological studies have identified obstructive sleep apnea (OSA) as a risk factor for systemic hypertension, but a direct etiologic link between the two disorders has not been established definitively. Furthermore, the specific physiological mechanisms underlying the association between OSA and systemic hypertension have not been identified. The purpose of this study was to systematically examine the effects of OSA on daytime and nighttime blood pressure (BP). We induced OSA in four dogs by intermittent airway occlusion during nocturnal sleep. Daytime and nighttime BP were measured before, during, and after a 1-3-mo long period of OSA. OSA resulted in acute transient increases in nighttime BP to a maximum of 13.0+/-2.0 mmHg (mean+/-SEM), and eventually produced sustained daytime hypertension to a maximum of 15.7+/-4.3 mmHg. In a subsequent protocol, recurrent arousal from sleep without airway occlusion did not result in daytime hypertension. The demonstration that OSA can lead to the development of sustained hypertension has considerable importance, given the high prevalence of both disorders in the population.

Sleep architecture in a canine model of obstructive sleep apnea.

Obstructive sleep apnea (OSA) causes recurrent sleep disruption that is thought to contribute to excessive daytime sleepiness in patients with this disorder. The purpose of this study was to determine the specific effects of OSA on overall sleep architecture in a canine model of OSA. The advantage of this model is that sleep during long-term OSA can be compared to both normal sleep before OSA and recovery sleep after OSA. Studies were performed in four dogs in which sleep-wake state was monitored continuously by a computer that received telemetered EEG and EMG signals. Whenever sleep was detected, the computer sent a signal to close a valve through which the dog breathed; when the dog awoke the occlusion was released. In each dog, data were analyzed from 4 consecutive nights in three phases: a control phase before induction of OSA, a phase during long-term OSA (mean = 85 days, apnea index = 59/hour), and a recovery phase after cessation of OSA. During recovery there was a significant increase in the amount of rapid-eye-movement (REM) sleep compared to the OSA phase (p < 0.01), as well as significant increases in sleep efficiency and decreases in wakefulness (p < 0.01), similar to that reported in OSA patients. The REM rebound during recovery, however, could not be attributed to overall REM deprivation since the amount of REM sleep during the OSA phase was not different from the control phase (p = 0.708). This finding suggests that REM rebound during recovery from OSA is not the result of an overall REM sleep deficit per se. Rather, repeated sleep disruption due to the effects of repetitive apneas and hypoxia may lead to an increased REM sleep drive that manifests itself as a REM sleep rebound during recovery sleep after OSA.

Effect of changing venoarterial pH difference on in vivo arterial pH.

Plasma pH has been postulated to change slowly in blood leaving the pulmonary capillaries because of the uncatalyzed dehydration of CO2. If so, there could be a difference between in vivo and in vitro arterial pH, the magnitude of which would be dependent on the venoarterial pH difference (v-aDpH). We tested this hypothesis in anesthetized dogs by changing v-aDpH by airway CO2 loading and by comparing arterial pH measured in vivo by a rapidly responding intravascular pH electrode with that measured in vitro by a conventional glass electrode. Using a multiple regression analysis, we found a small but significant contribution of venous pH to in vivo arterial pH, with a regression coefficient of 0.0718 (P less than 0.0001), suggesting a postcapillary increase of in vivo arterial pH. When carbonic anhydrase was inhibited by the administration of acetazolamide, the effect of venous pH on arterial pH was abolished, and a unique relationship between in vivo and in vitro arterial pH was established (regression coefficient 1.02; P greater than 0.05, comparison with unity). These results could be accounted for in a computer simulation of gas exchange among alveolus, plasma, and erythrocyte. We conclude that there exists a small but measurable postcapillary increase in arterial pH.

Tonic respiratory drive in the absence of rhythm generation in the conscious dog.

This study was designed to determine whether a chemoreceptor-mediated tonic respiratory drive exists below the apneic threshold. Expiratory (triangularis sterni) and inspiratory (diaphragm and parasternal intercostal) electromyographic activities were recorded in three awake relaxed dogs breathing through an endotracheal tube inserted into a permanent tracheostomy. The cervical vagus nerves were cold blocked to avoid the complicating effects of vagal inputs on respiratory activity. During hypocapnia produced by mechanical hyperventilation, expiratory muscle activity converted from rhythmic to tonic discharge when inspiratory muscle activity and spontaneous breathing movements were abolished. In hypocapnia, changes in arterial PCO2 (in hyperoxia) were produced by changing the ventilator rate for steady-state (> 6 min) CO2 stimuli and by disconnecting the ventilator for transient CO2 stimuli. By use of either method, a CO2-mediated drive to the expiratory muscle was consistently observed during hypocapnic apnea. At a constant level of hypocapnia, inhalation of 5% O2 consistently caused the onset of spontaneous breathing; the onset of phasic inspiratory activity was associated with reciprocal inhibition of the tonic expiratory activity. However, inhalation of 10 and 15% O2 caused an inhibition of the tonic expiratory activity, even without the onset of breathing. These results suggest that the response threshold of the respiratory chemoreceptors is lower than the apneic threshold and that a chemoreceptor-mediated tonic respiratory drive persists during apnea.

Single breath of CO2 as a clinical test of the peripheral chemoreflex.

Peripheral chemoreceptor responsiveness is usually examined clinically by hypoxic testing, but the usefulness of this approach is limited by safety considerations, and the interpretation of results may be confounded by the direct central nervous system effects of hypoxia. Therefore we examined the single-breath (SB) CO2 test to determine its reproducibility and applicability as a clinical test of peripheral chemoreceptor function. The technique involved the inhalation of a SB of 13% CO2 in air. The ventilatory response was determined from the increase in ventilation (VE) during the first 20 s after the test breath and from the difference in end-tidal PCO2 between the test breath and preceding control breaths. The peak increase in VE occurred during the second or third breath after the test breath, corresponding to a delay of approximately 10 s. The mean of 10 SB tests administered at 2- to 3-min intervals was taken as the subject's response. Five healthy subjects were tested in this manner on each of 6 consecutive days with the response having an interday coefficient of variation of 25 +/- 6% (SD). The response in 26 healthy females (aged 22-61 yr) was 0.32 +/- 0.11 l.min-1.Torr-1, and in 26 healthy males (aged 24-69 yr) the response was 0.38 +/- 0.14 (P NS). No significant correlation was found between the age of the subjects and their ventilatory response. Thirty-six of the subjects also underwent hyperoxic CO2 rebreathing tests, the response to which is dependent on central chemoreceptor function. No correlation was found between rebreathing and SB tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory-related heart rate variability persists during central apnea in dogs: mechanisms and implications.

The aim of this study was to determine the mechanism(s) responsible for the persistence of respiratory sinus arrhythmia (RSA) during central apnea. In five awake dogs, heart rate (HR) was recorded during constant mechanical ventilation (MV) and during central apneas produced by cessation of MV. For each of 10 control ventilator cycles before MV was stopped, instantaneous HR was plotted against the time from the onset of lung inflation; the fundamental and first harmonic of a sine wave (at the ventilator frequency) was then fitted to the HR data. For the control cycles, the mean r2 from the curve fits was 0.57 +/- 0.07, showing that a significant component of the HR variability was linked to the ventilator cycle. After MV was stopped, RSA persisted and only by the third "phantom" ventilator cycle during apnea had the degree of fit consistently decreased compared with control dogs (P < 0.02). The persistence of ventilator-linked RSA at the onset of central apnea supports the concept of a "memory" in the respiratory system. Toward the end of central apnea, HR variability reappeared and had the periodicity and rhythmic profile of RSA on 81% of occasions. The presence of RSA-like activity toward the end of central apnea suggests that subthreshold rhythmic respiratory-related activity may be present even before the onset of detectable lung volume changes.

Effect of inspiratory muscle unloading on arousal responses to CO2 and hypoxia in sleeping dogs.

Chemical respiratory stimuli can induce arousal from sleep, but the specific mechanisms involved have not been established. Therefore, we tested the hypothesis that mechanoreceptor stimuli arising in the ventilatory apparatus have a role in the arousal responses to progressive hypercapnia and hypoxia by comparing arousal responses during spontaneous ventilation with those obtained when the inspiratory muscles were unloaded by mechanical ventilatory assistance. Studies were performed in three trained dogs in which the adequacy of inspiratory muscle unloading was verified by diaphragmatic electromyographic (EMG) recordings. In rapid-eye-movement (REM) sleep the arousal threshold during progressive hypercapnia increased from 68.4 +/- 0.5 (SE) mmHg during spontaneous runs to 72.3 +/- 0.8 mmHg during mechanically assisted runs (P < 0.01). In contrast there were no changes in arousal responses to hypercapnia during non-REM (NREM) sleep or to hypoxia in either NREM or REM sleep. However, during the assisted hypoxic runs, EMG activity of the transversus abdominis muscle was increased compared with the unassisted runs; therefore, the effects on arousal threshold of unloading the inspiratory muscles may have been offset by increased loading of the expiratory muscles. The findings indicate that even in the absence of added mechanical loads, mechanoreceptor stimuli probably arising in the respiratory muscles contribute to the arousal response to hypercapnia during REM sleep.

Immediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs.

To determine the immediate effects of arousal from non-rapid-eye-movement (non-REM) sleep on cardiac sympathetic and parasympathetic activities, six dogs were studied breathing through an endotracheal tube inserted into a chronic tracheostomy. Mean heart rates (HRs) during non-REM sleep were compared with 1) awake periods immediately after spontaneous arousals (ARs) and 2) later periods of stable relaxed wakefulness (RW). During spontaneous breathing, HR increased after AR (mean = 31.0%; P < 0.001) and in RW (mean = 7.6%; P < 0.001). To avoid the confounding influence of changes in breathing pattern, lung volume, and blood gases accompanying AR on HR, further studies were performed during constant mechanical hyperventilation that eliminated spontaneous breathing. In this condition, HR still increased after AR (mean = 29.9%; P < 0.001) and in RW (mean = 5.7%; P < 0.001), suggesting that the HR increases could be mediated by an effect of the state change per se on autonomic activity. This interpretation was confirmed when the HR increases were essentially abolished by combined cardiac sympathetic and parasympathetic block. In contrast, parasympathetic block alone did not prevent the HR increases after AR (mean = 12.2%; P < 0.001) or in RW (mean = 12.3%; P < 0.001), whereas sympathetic block alone almost abolished the HR increases in RW (mean = 3.6%) but did not prevent the HR increases during AR (mean = 30.2%; P < 0.001). The results show that, compared with non-REM sleep, AR is associated with acute cardiac sympathetic activation and parasympathetic withdrawal, whereas stable RW is associated mainly with sympathetic activation. These effects may have clinical relevance to the cardiovascular sequelae of breathing disorders that cause repetitive arousals from sleep.

Role of upper airway in ventilatory control in awake and sleeping dogs.

We examined the role of the upper airway in the regulation of the pattern of breathing in six adult dogs during wakefulness and sleep. The dogs breathed through a fenestrated endotracheal tube inserted through a tracheostomy. The tube was modified to allow airflow to be directed either through the nose or through the tracheostomy. When airflow was diverted from nose to tracheostomy there was an abrupt increase in the rate of expiratory airflow, resulting in prolongation of the end-expiratory pause but no change in overall expiratory duration or respiratory frequency. Furthermore, electromyogram recordings from implanted diaphragmatic and laryngeal muscle electrodes did not show any changes that could be interpreted as an attempt to delay expiratory airflow or increase end-expiratory lung volume. The effects of switching from nose to tracheostomy breathing could be reversed by adding a resistance to the endotracheal tube so as to approximate upper airway resistance. The findings indicate that under normal conditions in the adult dog upper airway receptors play little role in regulation of respiratory pattern and that the upper airway exerts little influence on the maintenance of end-expiratory lung volume.

Abdominal muscle activation by respiratory stimuli in conscious dogs.

The responses of the diaphragm, external oblique, and transversus abdominis muscles to hyperoxic hypercapnia and isocapnic hypoxia were studied in four awake dogs to test the hypothesis that central and peripheral chemoreceptor inputs result in different patterns of respiratory muscle activation. The dogs were trained to lie quietly in place, and electromyographic (EMG) discharges of the diaphragm (EMGdi), external oblique (EMGeo), and transversus abdominis (EMGta) were recorded from chronically implanted electrodes. Both hypercapnia and hypoxia recruited EMGeo and EMGta activity, but at comparable levels of minute volume of ventilation the EMG activity of the abdominal muscles was greater during hypercapnia than during hypoxia. However the two chemical stimuli also resulted in different tidal volume (VT) and respiratory frequency responses at any given minute volume of ventilation. When EMG activity was reanalyzed as a function of VT, EMGeo and EMGta were the same for a given VT whether induced by hypercapnia or hypoxia, but EMGdi was consistently greater during hypoxia than during hypercapnia. When the vagus nerves were blocked by cooling exteriorized cervical vagal loops, all abdominal muscle EMG activity was abolished. The findings support the concept that stimulation of the central and peripheral chemoreceptors results in asymmetric activation of the inspiratory and expiratory respiratory muscles. The findings also indicate that afferent vagal stimuli play an important facilitatory role in activation of the abdominal expiratory muscles.

Canine model of obstructive sleep apnea: model description and preliminary application.

This report describes a canine model of obstructive sleep apnea (OSA) developed in our laboratory and the results of its preliminary short-term application. Healthy adult dogs were prepared with a tracheostomy and with implanted electroencephalographic and nuchal electromyographic recording electrodes. A silent occlusion valve was attached to the outer end of the endotracheal tube. The electroencephalogram and electromyogram were monitored continuously by a computer that determined sleep-wake state using software developed in our laboratory. At a predetermined time (e.g., 12 s) after each sleep onset, a signal was transmitted from the computer to the valve controller, resulting in airway occlusion. When the dog aroused from sleep, the occlusion was released. These events therefore mimic those that occur in human OSA. Successful operation of the model was confirmed during 5-day continuous trials in two dogs. During the trials, the dogs became increasingly somnolent both by behavioral observation and objective measurement. The frequency of occlusions increased, and measures of apnea severity, including apnea duration and end-apneic arterial oxygen saturation, worsened. We conclude that this experimental model of repeated airway occlusion during sleep provides a potentially powerful tool for investigating the sequelae of OSA.

Validation of a telemetry system for long-term measurement of blood pressure.

We have used an implanted telemetry system to continuously monitor blood pressure (BP) in three dogs for durations ranging from 28 to 75 wk after implantation. Measurements of BP obtained by telemetry were compared every 3-12 wk, with measurements of BP recorded with a manometer-tipped catheter that was inserted into a femoral artery. Over a wide range of both physiological and pharmacologically manipulated pressures (40-200 mmHg), the values of BP obtained by the two methods were highly correlated (all r > 0.966; all P < or = 0.0001). However, the mean differences between the values obtained by the two systems were different from zero (range +29.6 to -1.5 mmHg; P < or = 0.0001), indicating an offset in the BP values recorded from the implanted system. Furthermore, this offset was dependent on the absolute level of the BP. The findings indicate that, for a period of at least 28 wk and up to 75 wk after implantation, the telemetry system accurately measures acute changes in BP and can reliably measure absolute BP provided that the system is properly validated.

Physiological determinants of nocturnal arterial oxygenation in patients with obstructive sleep apnea.

Among patients with similar degrees of obstructive sleep apnea (OSA) there is considerable variability in the degree of associated nocturnal hypoxemia. The factors responsible for this variability have not been clearly defined. Therefore we studied 44 patients with OSA to identify the physiological determinants of nocturnal arterial O2 saturation (SaO2). All patients underwent pulmonary function testing, arterial blood gas analysis, and overnight polysomnography. Mean nocturnal SaO2 ranged from 96 to 66% and apnea-hypopnea index from 11 to 128 per hour of sleep. Several anthropometric, respiratory physiological, and polysomnographic variables that could be expected to influence nocturnal SaO2 were entered into a stepwise multiple linear regression analysis, with mean nocturnal SaO2 as the dependent variable. Three variables [awake supine arterial PO2 (PaO2), expiratory reserve volume, and percentage of sleep time spent in apnea] were found to correlate strongly with mean nocturnal SaO2 (multiple R, 0.854; P less than 0.0001) and accounted for 73% of its variability among patients. Body weight, other lung volumes, and airflow rates influenced awake PaO2 and expiratory reserve volume but had no independent influence on nocturnal SaO2. In a further group of 15 patients with OSA a high correlation was obtained between measured nocturnal SaO2 and that predicted by the model (r = 0.87; P less than 0.001). We conclude that derangements of pulmonary mechanics and awake PaO2 (generally attributable to obesity and diffuse airway obstruction) are of major importance in establishing the severity of nocturnal hypoxemia in patients with OSA.

Pathogenesis and pathophysiology of the obstructive sleep apnea syndrome.

OSA can be considered to arise as a result of the interaction of sleep-related changes in upper airway muscle function and subtle narrowing of the oropharyngeal lumen. The resulting apnea-induced asphyxia leads to an arousal response that terminates the obstructive event. Recurrent episodes of nocturnal asphyxia and recurrent arousals from sleep induce a series of secondary physiological responses that may eventually produce the clinical cardiovascular, hemodynamic, and neuropsychiatric manifestations of the OSA syndrome. The specific factors responsible for each of the clinical features of OSA are not fully understood. Nevertheless, as reviewed here, many of the mechanisms involved have been defined in recent years. Thus, during the past decade OSA has evolved from a disorder that was virtually unrecognized clinically to one whose pathogenetic and pathophysiological mechanisms are to a large extent well understood.

Central sleep apnea.

The critical issue in considering the diagnosis and management of CSA is to determine the physiologic process underlying the disorder. CSA includes a pathophysiologically and clinically heterogeneous group of disorders that can be divided into two main groups on the basis of the awake PaCO2: a hypercapnic group, in whom the disorder is related to central alveolar hypoventilation or neuromuscular disease, and a nonhypercapnic group, in whom there is no identifiable underlying disorder. The common feature of these two groups is recurrent episodes of central apnea during sleep related to withdrawal of the wakefulness drive to breathing. In the hypercapnic group the clinical history is dominated by recurrent episodes of respiratory failure and its complications, with the sleep disturbance being a secondary feature. CSA in these patients is simply an exaggeration, by sleep, of their hypoventilation disorder. Treatment in most cases involves mechanical assisted ventilation during sleep, which can be very effective in reversing CSA and respiratory failure. In contrast, idiopathic CSA is characterized by a tendency to hyperventilation. This tendency is reinforced during sleep by recurrent arousals, which tend to propagate the CSA. Unlike hypercapnic CSA, idiopathic CSA is a relatively benign condition in which cardiorespiratory failure is not a feature. Treatment of this disorder is problematic, but the use of nocturnal nasal CPAP appears to be quite effective.

Nasal surgery in the management of sleep apnea.

We present our experience with short- and long-term beneficial results obtained from surgery of the nasal valve area in carefully selected patients with obstructive sleep apnea (OSA). In six cases reported here, surgical treatment resulted in subjective improvement in snoring and daytime somnolence. Objective improvement was noted in three patients who had nasal valve area obstruction. Although the role of surgery in patients with mild OSA needs further assessment, surgical correction of nasal valve area obstruction in patients with moderately severe to severe OSA appears clearly indicated.

Regulation of respiration by bronchopulmonary receptors in conscious dogs.

In awake dogs, the Hering-Breuer inflation reflex (HBIR) was present but weaker than during anaesthesia. Auditory or visual distraction, increased body temperature, and exercise decreased or abolished HBIR. Bilateral complete vagal blockade resulted in slow deep breathing, but arterial PCO2, and apnoeic threshold PCO2, were unafected. Vagal blockade decreased the response of frequency of respiration during hypoxemia and hypercapnia, but did not affect the response to increasing body temperature or to exercise. Progressive cooling of the exteriorized vagal loops from 16 to 9 degrees Celsius resulted in progressive abolition of HBIR, but the respiratory response to inhaled histamine was unaffected. There was a decrease in the expiratory phase of respiration and in tidal volume; the dogs hyperventilated at rest and had an increased respiratory response to inhaled CO2. Further cooling of the vagal loops sufficient to abolish the respiratory response to inhaled histamine resulted in the slow, deep breathing pattern and impaired respiratory frequency response to inhaled CO2 typical of the completely vagotomized animal.