Apneic Threshold Research Articles

Central Sleep Apnea and Cheyne-Stokes Respiration

Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) is a form of periodic breathing, commonly observed in patients with heart failure (HF), in which central apneas alternate with hyperpneas that have a waxing-waning pattern of tidal volume. Uniform criteria by which to diagnose a clinically significant degree of CSR-CSA have yet to be established. CSR-CSA is caused by respiratory control system instability characterized by a tendency to hyperventilate. Central apnea occurs when Pa(CO(2)) falls below the threshold for apnea during sleep due to ventilatory overshoot. Patients with CSR-CSA are generally hypocapnic, with a Pa(CO(2)) closer than normal to the apneic threshold such that even slight augmentation in ventilation drives Pa(CO(2)) below threshold and triggers apnea. Factors contributing to hyperventilation in HF include stimulation of pulmonary irritant receptors by pulmonary congestion, increased chemoreceptor sensitivity, reduced cerebrovascular blood flow, and recurrent arousals from sleep. Controversy remains as to whether CSR-CSA is simply a reflection of HF severity, or whether it exerts unique adverse effects on prognosis. The main adverse influence of CSR-CSA on cardiovascular function appears to be excessive sympathetic nervous system activity due to apnea-related hypoxia and arousals from sleep. A number of studies have examined the potential relationship between CSR-CSA and mortality in HF. Most reported that CSR-CSA was associated with an increased risk for mortality, but these studies were small. Further research is therefore needed to elucidate mechanisms which contribute to the pathogenesis of CSR-CSA, and to determine whether its treatment can reduce morbidity and mortality in patients with HF.

The critical Role of CO2 on Respiratory Control, PeriodicBreathing and Apnea in Neonates

Background- CO2 is a gas present in the atmosphere. Its linear shaped molecule contains two double bonds linking carbon and oxygen. It was discovered in 1630 by Jan Van Helmont who obtained the CO2 by fermenting grape and burning coal. From the beginning it was clear that CO2 is essential to life due to its warming effect on the planet and its role in photosynthesis. In the beginning of the 20th century Haldane (1905) first suggested that breathing is controlled by a negative feedback system in which CO2 is both the controlled and the controller variable. Phillipson and others have shown that without CO2 breathing is absent. During most of the last century the consensus was that CO2 acted centrally on the rostral ventro-lateral surface of the medulla oblongata (Loeschcke;1958, Mitchell, 1963) Only in the end of the last century this action was located on the respiratory neurons of the Pre-Bötzinger region. These are inspiratory pacemakers neurons highly sensitive to CO2. The dendrites of these neurons are located adjacent to the surface of the medulla previously thought to be responsible for this response. The CO2 receptors of these cells are likely to be located in the dendrites of these neurons, mimicking CO2 receptors described for more primitive species, but this has not yet been documented. Breathing Pattern- CO2 is known to be a powerful regularizer of breathing pattern. Our observations show that the coefficient of variability of tidal volume is much less with CO2 than with other regularizers of breathing, such as O2 or Methylxanthines. The CO 2Threshold-Our data in 16 preterm and 16 term infants (JAP 98:1171–76,2005) suggested that periodic breathing occurs due to a periodic fall in baseline PCO2 below the apneic threshold (CO2 level below which breathing stops). InhaledCO2 to Treat Apnea- When assessed in the clinical laboratory, under strict administration control, both CO2 and theophylline decreased apnea time by 71%, and prolonged apnea (=20s) by 92% (n=20). When measured in the Nursery, in a double blind randomized control trial, inhalation of 1% CO2 and theophylline decreased apnea time by 68% and 49% respectively (Pediat Res: 106, 2, 2007; n=79). Prolonged apneas also decreased by 87% and 33%. The fall was always more pronounced with theophylline. Seven infants with residual lung disease did not respond to CO2, but responded to CPAP. Adverse side effects such as tachypnea, tachycardia, emesis and jitteriness predominated with theophylline. We surmised that CO2 inhalation may be a safe alternative to theophylline in the treatment of apnea of prematurity in infants without residual lung disease.

Chronic intermittent hypoxia increases the CO2 reserve in sleeping dogs

We hypothesized that chronic intermittent hypoxia (CIH) would induce a predisposition to apnea in response to induced hypocapnia. To test this, we used pressure support ventilation to quantify the difference in end-tidal partial pressure of CO(2) (Pet(CO(2))) between eupnea and the apneic threshold ("CO(2) reserve") as an index of the propensity for apnea and unstable breathing during sleep, both before and following up to 3-wk exposure to chronic intermittent hypoxia in dogs. CIH consisted of 25 s of Pet(O(2)) = 35-40 Torr followed by 35 s of normoxia, and this pattern was repeated 60 times/h, 7-8 h/day for 3 wk. The CO(2) reserve was determined during non-rapid eye movement sleep in normoxia 14-16 h after the most recent hypoxic exposure. Contrary to our hypothesis, the slope of the ventilatory response to CO(2) below eupnea progressively decreased during CIH (control, 1.36 +/- 0.18; week 2, 0.94 +/- 0.12; week 3, 0.73 +/- 0.05 l.min(-1).Torr(-1), P < 0.05). This resulted in a significant increase in the CO(2) reserve relative to control (P < 0.05) following both 2 and 3 wk of CIH (control, 2.6 +/- 0.6; week 2, 3.7 +/- 0.8; week 3, 4.5 +/- 0.9 Torr). CIH also 1) caused no change in eupneic, air breathing Pa(CO(2)); 2) increased the slope of the ventilatory response to hypercapnia after 2 wk but not after 3 wk compared with control; and 3) had no effect on the ventilatory response to hypoxia. We conclude that 3-wk CIH reduced the sensitivity of the ventilatory response to transient hypocapnia and thereby increased the CO(2) reserve, i.e., the propensity for apnea was reduced.

The apneic threshold during non-REM sleep in dogs: sensitivity of carotid body vs. central chemoreceptors

The relative importance of peripheral vs. central chemoreceptors in causing apnea/unstable breathing during sleep is unresolved. This has never been tested in an unanesthetized preparation with intact carotid bodies. We studied three unanesthetized dogs during normal sleep in a preparation in which intact carotid body chemoreceptors could be reversibly isolated from the systemic circulation and perfused. Apneic thresholds and the CO(2) reserve (end-tidal Pco(2) eupneic - end-tidal Pco(2) apneic threshold) were determined using a pressure support ventilation technique. Dogs were studied when both central and peripheral chemoreceptors sensed transient hypocapnia induced by the pressure support ventilation and again with carotid body isolation such that only the central chemoreceptors sensed the hypocapnia. We observed that the CO(2) reserve was congruent with4.5 Torr when the carotid chemoreceptors sensed the transient hypocapnia but more than doubled (>9 Torr) when only the central chemoreceptors sensed hypocapnia. Furthermore, the expiratory time prolongations observed when only central chemoreceptors were exposed to hypocapnia differed from those obtained when both the central and peripheral chemoreceptors sensed the hypocapnia in that they 1) were substantially shorter for a given reduction in end-tidal Pco(2), 2) showed no stimulus: response relationship with increasing hypocapnia, and 3) often occurred at a time (>45 s) beyond the latency expected for the central chemoreceptors. These findings agree with those previously obtained using an identical pressure support ventilation protocol in carotid body-denervated sleeping dogs (Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. J Appl Physiol 94: 155-164, 2003). We conclude that hypocapnia sensed at the carotid body chemoreceptor is required for the initiation of apnea following a transient ventilatory overshoot in non-rapid eye movement sleep.

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.

Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story

since the 1970s, over 200 studies with acetazolamide have shown it safe and 60–80% effective in acute mountain sickness (AMS). Despite much investigation, our understanding of its action in AMS remains incomplete and more complicated than generally taught. This should come as no surprise

Exercise hyperpnea and hypercapnic ventilatory responses in women

We studied the relationship between exercise hyperpnea (i.e., ventilatory dynamics) at the onset of exercise and hypercapnic ventilatory response (HCVR), and their differences between the follicular (FP) and luteal (LP) phases of the menstrual cycle in six healthy females. HCVR was tested under three O(2) conditions: hyperoxia (FiO(2)=1.0), normoxia (0.21), and hypoxia (0.12). HCVR was defined as the relationship between the end-tidal P(CO2) and minute ventilation (V(E)) using the regression line of the CO(2) slope and a mimetically apneic threshold of CO(2). HCVR provocation and measurements were conducted using an inspired CO(2) concentration of up to approximately 8 mmHg higher than the end-tidal P(CO2) level of basal isocapnic the end-tidal P(CO2) at each menstrual both the slope and threshold in HCVR showed no statistically significant difference between LP and FP under any inspired FiO(2) conditions. In the case of exercise hyperpnea during the onset of submaximal exercise, the mean response time (MRT) in V(E) dynamics showed no significant difference between LP and FP. Consequently, MRT in V(E) response was not related to the slope in HCVR. During steady-state exercise, even though the V(E)/V(CO2) showed no significance between LP and FP, V(E)/V(CO2) was significantly related to the slope in HCVR (r=0.59, P<0.05). Exercise ventilation (i.e., V(E)/V(CO2)) would partly be adjusted by the enhancement of the chemoreflex drive to CO(2) only during the steady-state exercise.

Long-term Efficacy of Acetazolamide on Cheyne-Stokes Respiration in Congestive Heart Failure

We very much appreciated Dr. Javaheri’s recent article concerning the effects of acetazolamide on Cheyne-Stokes respiration (CSR) in congestive heart failure (1). Since CSR in heart failure, characterized by repetitive central apneas alternating with a crescendo–decrescendo tidal volume, is acknowledged to behighly prevalent (2) and probably can also be a therapeutic target, the article has relevance not only for pulmonary/sleep specialists but cardiologists as well. According to this study, acetazolamide was taken 1 h before bedtime for a week by heart failure patients with CSR. The author reported that apnea–hypopnea and nocturnal oxygen desaturation were ameliorated, subjective perception of sleep quality and daytime symptoms were improved, and PaCO2 in arterial blood gases was decreased. Although Dr. Javaheri suggested that a changing apneic threshold might have played a major role (1), other mechanisms could be considered, including the changes in controller/plant gains and circulation time. A further decline in PaCO2 secondary to the metabolic acidosis produced by acetazolamide may pose a risk of exaggerating CSR by jeopardizing respiratory stability. In a recent case series, five heart failure patients with CSR were treated nightly for a year with continuous positive airway pressure (CPAP) of 5–8 cm H2O, resulting in improved central sleep apnea, sleep quality, and cardiac function (3). An additional data analysis of ventilatory response to rebreathing hypercapnia in four of five normocapnic patients revealed that the slope of the regression line of minute ventilation versus PaCO2 was significantly decreased after 3 mo of CPAP, suggesting that chemoreceptor sensitivity was diminished after appropriate treatment. Dr. Javaheri did not show changes in chemosensitivity, but had previously reported that an enhanced sensitivity to CO2 could predispose some heart failure patients to develop CSR (4). Although the central action of acetazolamide might have improved daytime symptoms in heart failure patients (1), acetazolamide is a second-line diuretic for treatment of heart failure due to its adverse effects (such as hyperpnea, numbness, and nocturia) and pharmacologic acclimatization, which would occur within a few months after starting administration. Nonetheless, the long-term efficacy and safety of acetazolamide in improving CSR in heart failure has not yet been established. Sleep-disordered breathing is a major public health problem (5), and its interactionwith cardiac function has been called a new cardiovascular frontier (6), as indicated by the fact that only 17 yr have passed since one of the earliest prevalence studies dealing with CSR in heart failure appeared in a journal for cardiologists (2).

Long-term Efficacy of Acetazolamide on Cheyne-Stokes Respiration in Congestive Heart Failure

We very much appreciated Dr. Javaheri’s recent article concerning the effects of acetazolamide on Cheyne-Stokes respiration (CSR) in congestive heart failure (1). Since CSR in heart failure, characterized by repetitive central apneas alternating with a crescendo–decrescendo tidal volume, is acknowledged to behighly prevalent (2) and probably can also be a therapeutic target, the article has relevance not only for pulmonary/sleep specialists but cardiologists as well. According to this study, acetazolamide was taken 1 h before bedtime for a week by heart failure patients with CSR. The author reported that apnea–hypopnea and nocturnal oxygen desaturation were ameliorated, subjective perception of sleep quality and daytime symptoms were improved, and PaCO2 in arterial blood gases was decreased. Although Dr. Javaheri suggested that a changing apneic threshold might have played a major role (1), other mechanisms could be considered, including the changes in controller/plant gains and circulation time. A further decline in PaCO2 secondary to the metabolic acidosis produced by acetazolamide may pose a risk of exaggerating CSR by jeopardizing respiratory stability. In a recent case series, five heart failure patients with CSR were treated nightly for a year with continuous positive airway pressure (CPAP) of 5–8 cm H2O, resulting in improved central sleep apnea, sleep quality, and cardiac function (3). An additional data analysis of ventilatory response to rebreathing hypercapnia in four of five normocapnic patients revealed that the slope of the regression line of minute ventilation versus PaCO2 was significantly decreased after 3 mo of CPAP, suggesting that chemoreceptor sensitivity was diminished after appropriate treatment. Dr. Javaheri did not show changes in chemosensitivity, but had previously reported that an enhanced sensitivity to CO2 could predispose some heart failure patients to develop CSR (4). Although the central action of acetazolamide might have improved daytime symptoms in heart failure patients (1), acetazolamide is a second-line diuretic for treatment of heart failure due to its adverse effects (such as hyperpnea, numbness, and nocturia) and pharmacologic acclimatization, which would occur within a few months after starting administration. Nonetheless, the long-term efficacy and safety of acetazolamide in improving CSR in heart failure has not yet been established. Sleep-disordered breathing is a major public health problem (5), and its interactionwith cardiac function has been called a new cardiovascular frontier (6), as indicated by the fact that only 17 yr have passed since one of the earliest prevalence studies dealing with CSR in heart failure appeared in a journal for cardiologists (2).

Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog

Periodic breathing is commonly observed in chronic heart failure (CHF) when pulmonary capillary wedge pressure is abnormally high and there is usually concomitant tachypneic hyperventilation. We hypothesized that acute pulmonary hypertension at pressures encountered in CHF and involving all of the lungs and pulmonary vessels would predispose to apnea/unstable breathing during sleep. We tested this in a chronically instrumented, unanesthetized dog model during non-rapid eye movement (NREM) sleep. Pulmonary hypertension was created by partial occlusion of the left atrium by means of an implanted balloon catheter in the atrial lumen. Raising mean left atrial pressure by 5.7 +/- 1.1 Torr resulted immediately in tachypneic hyperventilation [breathing frequency increased significantly from 13.8 to 19.9 breaths/min; end-tidal P(CO2) (P(ET(CO2))) fell significantly from 38.5 to 35.9 Torr]. This tachypneic hyperventilation was present during wakefulness, NREM sleep, and rapid eye movement sleep. In NREM sleep, this increase in left atrial pressure increased the gain of the ventilatory response to CO2 below eupnea (1.3 to 2.2 l.min(-1).Torr(-1)) and thereby narrowed the CO2 reserve [P(ET(CO2)) (apneic threshold) - P(ET(CO2)) (eupnea)], despite the decreased plant gain resulting from the hyperventilation. We conclude that acute pulmonary hypertension during sleep results in a narrowed CO2 reserve and thus predisposes toward apnea/unstable breathing and may, therefore, contribute to the breathing instability observed in CHF.

Influence of arterial O2 on the susceptibility to posthyperventilation apnea during sleep

To investigate the contribution of the peripheral chemoreceptors to the susceptibility to posthyperventilation apnea, we evaluated the time course and magnitude of hypocapnia required to produce apnea at different levels of peripheral chemoreceptor activation produced by exposure to three levels of inspired P(O2). We measured the apneic threshold and the apnea latency in nine normal sleeping subjects in response to augmented breaths during normoxia (room air), hypoxia (arterial O2 saturation = 78-80%), and hyperoxia (inspired O2 fraction = 50-52%). Pressure support mechanical ventilation in the assist mode was employed to introduce a single or multiple numbers of consecutive, sigh-like breaths to cause apnea. The apnea latency was measured from the end inspiration of the first augmented breath to the onset of apnea. It was 12.2 +/- 1.1 s during normoxia, which was similar to the lung-to-ear circulation delay of 11.7 s in these subjects. Hypoxia shortened the apnea latency (6.3 +/- 0.8 s; P < 0.05), whereas hyperoxia prolonged it (71.5 +/- 13.8 s; P < 0.01). The apneic threshold end-tidal P(CO2) (Pet(CO2)) was defined as the Pet(CO2)) at the onset of apnea. During hypoxia, the apneic threshold Pet(CO2) was higher (38.9 +/- 1.7 Torr; P < 0.01) compared with normoxia (35.8 +/- 1.1; Torr); during hyperoxia, it was lower (33.0 +/- 0.8 Torr; P < 0.05). Furthermore, the difference between the eupneic Pet(CO2) and apneic threshold Pet(CO2) was smaller during hypoxia (3.0 +/- 1.0 Torr P < 001) and greater during hyperoxia (10.6 +/- 0.8 Torr; P < 0.05) compared with normoxia (8.0 +/- 0.6 Torr). Correspondingly, the hypocapnic ventilatory response to CO2 below the eupneic Pet(CO2) was increased by hypoxia (3.44 +/- 0.63 l.min(-1).Torr(-1); P < 0.05) and decreased by hyperoxia (0.63 +/- 0.04 l.min(-1).Torr(-1); P < 0.05) compared with normoxia (0.79 +/- 0.05 l.min(-1).Torr(-1)). These findings indicate that posthyperventilation apnea is initiated by the peripheral chemoreceptors and that the varying susceptibility to apnea during hypoxia vs. hyperoxia is influenced by the relative activity of these receptors.

Ventilation is unstable during drowsiness before sleep onset

Ventilation is unstable during drowsiness before sleep onset. We have studied the effects of transitory changes in cerebral state during drowsiness on breath duration and lung volume in eight healthy subjects in the absence of changes in airway resistance and fluctuations of ventilation and CO2 tension, characteristic of the onset of non-rapid eye movement sleep. A volume-cycled ventilator in the assist control mode was used to maintain CO2 tension close to that when awake. Changes in cerebral state were determined by the EEG on a breath-by-breath basis and classified as alpha or theta breaths. Breath duration and the pause in gas flow between the end of expiratory airflow and the next breath were computed for two alpha breaths which preceded a theta breath and for the theta breath itself. The group mean (SD) results for this alpha-to-theta transition was associated with a prolongation in breath duration from 5.2 (SD 1.3) to 13.0 s (SD 2.1) and expiratory pause from 0.7 (SD 0.4) to 7.5 s (SD 2.2). Because the changes in arterial CO2 tension (PaCO2) are unknown during the theta breaths, we made in two subjects a continuous record of PaCO2 in the radial artery. PaCO2 remained constant from the alpha breaths through to the expiratory period of the theta breath by which time the duration of breath was already prolonged, representing an immediate and altered ventilatory response to the prevailing PaCO2. In the eight subjects, the CO2 tension awake was 39.6 Torr (SD 2.3) and on assisted ventilation 38.0 Torr (1.4). We conclude that the ventilatory instability recorded in the present experiments is due to the apneic threshold for CO2 being at or just below that when awake.

Pulmonale Hypertonie und schlafbezogene Atmungsstörungen

Pulmonary hypertension (PH), i. e. an increase of mean pulmonary artery pressure above 20 mm Hg under resting conditions, can be observed in different forms of sleep-disordered breathing (SDB). In obstructive sleep apnea (OSA) the apnea-associated triggers of hypoxia and intrathoracic pressure swings lead to repetitive rises of pulmonary artery pressure during sleep. In 20 - 30 % of these patients daytime PH occurs. PH in the setting of OSA is usually mild and rarely causes clinically evident cor pulmonale. Effective CPAP therapy has a beneficial influence on pulmonary hemodynamics in OSA. Severe congestive heart failure (i. e. with a LVEF < 40 %) might provoke pulmonary venous hypertension and thereby stimulation of pulmonary stretch and irritant receptors. The ensuing hyperventilation leads to a decrease of pCO (2) levels below the apneic threshold and thus contributes to the emergence of Cheyne Stokes respiration (CSR) in up to one half of the affected patients. Patients suffering from advanced idiopathic pulmonary arterial hypertension (IPAH) might show a similar breathing pattern while asleep. Possible pathogenetic factors of the nocturnal periodic breathing occurring in end-stage IPAH are prolonged circulation times and hypocapnia. In conclusion, SDB might cause PH (OSA-associated PH). On the other hand, PH might lead to the development of SDB (CSR in congestive heart failure, periodic breathing in IPAH).

Measurement of the CO2apneic threshold in newborn infants: possible relevance for periodic breathing and apnea

We measured the PCO2 apneic threshold in preterm and term infants. We hypothesized that, compared with adult subjects, the PCO2 apneic threshold in neonates is very close to the eupneic PCO2, likely facilitating the appearance of periodic breathing and apnea. In contrast with adults, who need to be artificially hyperventilated to switch from regular to periodic breathing, neonates do this spontaneously. We therefore measured the apneic threshold as the average alveolar PCO2 (PaCO2) of the last three breaths of regular breathing preceding the first apnea of an epoch of periodic breathing. We also measured the PaCO2 of the first three breaths of regular breathing after the last apnea of the same periodic breathing epoch. In preterm infants, eupneic PaCO2 was 38.6 +/- 1.4 Torr, the preperiodic PaCO2 apneic threshold was 37.3 +/- 1.4 Torr, and the postperiodic PaCO2 was 37.2 +/- 1.4 Torr. In term infants, the eupneic PaCO2 was 39.7 +/- 1.1 Torr, the preperiodic PaCO2 apneic threshold was 38.7 +/- 1.0 Torr, and the postperiodic value was 37.9 +/- 1.2 Torr. This means that the PaCO2 apneic thresholds were 1.3 +/- 0.1 and 1.0 +/- 0.2 Torr below eupneic PaCO2 in preterm and term infants, respectively. The transition from eupneic PaCO2 to PaCO2 apneic threshold preceding periodic breathing was accompanied by a minor and nonsignificant increase in ventilation, primarily related to a slight increase in frequency. The findings suggest that neonates breathe very close to their PCO2 apneic threshold, the overall average eupneic PCO2 being only 1.15 +/- 0.2 Torr (0.95-1.79, 95% confidence interval) above the apneic threshold. This value is much lower than that reported for adult subjects (3.5 +/- 0.4 Torr). We speculate that this closeness of eupneic and apneic PCO2 thresholds confers great vulnerability to the respiratory control system in neonates, because minor oscillations in breathing may bring eupneic PCO2 below threshold, causing apnea.

Hypocapnia Is Not a Predictor of Central Sleep Apnea in Patients with Cirrhosis

During sleep, maintenance of rhythmic breathing is critically dependent on the level of PCO(2), such that if the prevailing spontaneous PCO(2) decreases below the apneic threshold, central sleep apnea (CSA) occurs. Several studies have shown that in patients with systolic heart failure (SHF), presence of a low, awake arterial PCO(2) (Pa(CO(2))) increases the likelihood of developing CSA during sleep. We therefore sought to determine if a low Pa(CO(2)) is a predictor of CSA in patients with cirrhosis of the liver and with normal left ventricular systolic function. In 13 hypocapnic (Pa(CO(2)) < 36 mm Hg, mean = 33 mm Hg) patients with SHF and a mean left ventricular ejection fraction of 23%, the mean apnea-hypopnea index, was 28/hour. CSA accounted for most of the breathing disorders. In 10 hypocapnic (Pa(CO(2)) < 36 mm Hg, mean = 32 mm Hg) patients with cirrhosis and a normal left ventricular ejection fraction (60%), the mean apnea-hypopnea index was 2/hour. The maximum central apnea index was 0.2/hour. There were no significant differences in age, demographics, pulmonary function tests, Pa(O(2)), Pa(CO(2)), minute and alveolar ventilation, and ventilatory responses to CO(2) between the two groups. We conclude that, in contrast to SHF, presence of hypocapnia does not predict CSA in cirrhosis.

Increased propensity for apnea via dopamine-induced carotid body inhibition in sleeping dogs

We determined the effects of specific carotid body chemoreceptor inhibition on the propensity for apnea during sleep. We reduced the responsiveness of the carotid body chemoreceptors using intravenous dopamine infusions during non-rapid eye movement sleep in six dogs. Then we quantified the difference in end-tidal Pco(2) (Pet(CO(2))) between eupnea and the apneic threshold, the "CO(2) reserve," by gradually reducing Pet(CO(2)) transiently with pressure support ventilation at progressively increased tidal volume until apnea occurred. Dopamine infusions decreased steady-state eupneic ventilation by 15 +/- 6%, causing a mean CO(2) retention of 3.9 +/- 1.9 mmHg and a brief period of ventilatory instability. The apneic threshold Pet(CO(2)) rose 5.1 +/- 1.9 Torr; thus the CO(2) reserve was narrowed from -3.9 +/- 0.62 Torr in control to -2.7 +/- 0.78 Torr with dopamine. This decrease in the CO(2) reserve with dopamine resulted solely from the 20.5 +/- 11.3% increase in plant gain; the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal. We conclude that specific carotid chemoreceptor inhibition with dopamine increases the propensity for apnea during sleep by narrowing the CO(2) reserve below eupnea. This narrowing is due solely to an increase in plant gain as the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal control. These findings have implications for the role of chemoreceptor inhibition/stimulation in the genesis of apnea and breathing periodicity during sleep.

Pacemaker therapy in sleep apnea syndrome

Sleep apnea syndrome (SAS) is a serious health problem that particularly afflicts patients with cardiovascular disease. Pathophysiologically, an obstructive form of SAS with loss of air flow despite thorax movements and a central form of SAS with simultaneous cessation of air flow and respiratory movements are distinguished. Central SAS is present in almost 50% of patients with severe heart failure (HF). It induces alternating bradycardia and tachycardia related to fluctuations of the vago-sympathetic tone. Suppression or reduction of heart rate fluctuations by pacing may mitigate sleep apnea. In HF with marked nocturnal bradycardia, increasing the heart rate may improve cardiac output, shorten circulation time and decrease pulmonary congestion, thus diminishing the apneic threshold. Potentially, stimulation of vagal and sympathetic nerve fibers behind the superior vena cava/right atrial junction by pacing may directly influence cardiac vagal or sympathetic afferent neurons reducing central sleep apnea episodes. In obstructive SAS, polysomnography characterizes a specific pattern of sleep apnea where bradycardia precedes the onset of apnea. This could result from hypervagotonia first inducing bradycardia and then apnea. Atrial overdrive pacing may counteract hypervagotonia by maintaining sympathetic activity. Pacing might not benefit obstructive SAS due to excessive adiposity, anatomical obstacles or unrelated to bradycardia. In the future, cardiac pacing might be considered as an ancillary therapy for SAS in patients with bradycardia and/or hypervagotonia during sleep. Larger studies need to confirm this hypothesis in patients without a conventional indication for pacing. Device recording of sleep apnea could become a powerful tool to guide SAS therapy.

Commentary

HIGHLIGHTED TOPICSOxygen Sensing in Health and DiseaseCommentaryGary C. SieckGary C. SieckPublished Online:01 Mar 2004https://doi.org/10.1152/japplphysiol.01327.2003MoreSectionsPDF (9 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations Understanding the critical role of oxygen sensing in the physiological states of health and disease is important to our understanding of disease processes. This issue of the Journal concludes the Highlighted Topics series on “Oxygen Sensing in Health and Disease” and includes two articles that warrant comment, as they represent significant contributions to our general understanding of the mechanisms underlying oxygen sensing.In the first featured article, “Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans,” Dr. J. Mateika and colleagues (2) discuss the influence of episodic hypoxia on ventilatory response. After exposing awake humans to episodic hypoxia, these investigators evaluated the acute ventilatory response to hypoxia in the presence of progressively increasing levels of carbon dioxide. Their study showed that the ventilatory response to hypercapnia/hypoxia, but not hypocapnia/hypoxia, was increased after exposure to episodic hypoxia. This response was evident even though elevated ventilation levels (i.e., long-term facilitation) were not observed immediately after exposure to episodic hypoxia. These findings may have important implications for the control of breathing in individuals who suffer from sleep apnea. Disproportionate increases in the ventilatory response to hypercapnia/hypoxia after exposure to episodic hypoxia could subsequently drive carbon dioxide levels below the apneic threshold. Consequently, a reduction in central respiratory drive to chest wall and upper airway muscles might occur, and activation of this phenomenon might thus promote apnea during sleep.The second featured article, “Facilitation of dopamine and acetylcholine release by intermittent hypoxia in PC12 cells: involvement of calcium and reactive oxygen species” by Dr. D.-K. Kim and colleagues (1), reports, for the first time, the effect of intermittent hypoxia on transmitter release during hypoxia and examines the underlying cellular mechanisms that are activated and lead to altered transmitter release. These investigators simultaneously monitored the release of dopamine and acetylcholine from both naive and intermittent hypoxia-conditioned PC12 cells by using two dedicated and highly sensitive HPLC systems combined with an electrochemical detection method. From these measurements, the authors made an intriguing observation, wherein hypoxia selectively facilitates the release of dopamine, but not acetylcholine, in naive cells. By contrast, hypoxia increased the release of both dopamine and acetylcholine in intermittent hypoxia-conditioned cells. Notably, the mechanisms that are activated by intermittent hypoxia and coupled to intermittent hypoxia-evoked transmitter release seem to be different from those activated during acute hypoxia. In naive cells, the entry of extracellular calcium appears to be critical for hypoxia-evoked dopamine release. On the contrary, intermittent hypoxia-induced transmitter release during hypoxia depends on the mobilization of calcium from intracellular stores through activation of inositol 1,4,5-trisphosphate receptors, as well as generation of reactive oxygen species. References 1 Kim DK, Natarajan N, Prabhakar NR, and Kumar GK. Facilitation of dopamine and acetylcholine release by intermittent hypoxia in PC12 cells: involvement of calcium and reactive oxygen species. J Appl Physiol 96: 1206-1215, 2004.Link | ISI | Google Scholar2 Mateika JH, Mendello C, Obeid D, and Badr MS. Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans. J Appl Physiol 96: 1197-1205, 2004.Link | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 96Issue 3March 2004Pages 1196-1196 Copyright & PermissionsCopyright © 2004 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01327.2003History Published online 1 March 2004 Published in print 1 March 2004 Metrics

The essential role of carotid body chemoreceptors in sleep apnea.

Sleep apnea is attributable, in part, to an unstable ventilatory control system and specifically to a narrowed "CO2 reserve" (i.e., the difference in P(a)CO2 between eupnea and the apneic threshold). Findings from sleeping animal preparations with denervated carotid chemoreceptors or vascularly isolated, perfused carotid chemoreceptors demonstrate the critical importance of peripheral chemoreceptors to the ventilatory responses to dynamic changes in P(a)CO2. Specifically, (i) carotid body denervation prevented the apnea and periodic breathing that normally follow transient ventilatory overshoots; (ii) the CO2 reserve for peripheral chemoreceptors was about one half that for brain chemoreceptors; and (iii) hypocapnia isolated to the carotid chemoreceptors caused hypoventilation that persisted over time despite a concomitant, progressive brain respiratory acidosis. Observations in both humans and animals are cited to demonstrate the marked plasticity of the CO2 reserve and, therefore, the propensity for apneas and periodic breathing, in response to changing background ventilatory stimuli.

Respiratory depression by tramadol in the cat: involvement of opioid receptors.

Tramadol hydrochloride (tramadol) is a synthetic opioid analgesic with a relatively weak affinity at opioid receptors. At analgesic doses, tramadol seems to cause little or no respiratory depression in humans, although there are some conflicting data. The aim of this study was to examine whether tramadol causes dose-dependent inhibitory effects on the ventilatory carbon dioxide response curve and whether these are reversible or can be prevented by naloxone. Experiments were performed in cats under alpha-chloralose-urethane anesthesia. The effects of tramadol and naloxone were studied by applying square-wave changes in end-tidal pressure of carbon dioxide (Petco2; 7.5-11 mmHg) and by analyzing the dynamic ventilatory responses using a two-compartment model with a fast peripheral and a slow central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and a single offset (apneic threshold). In five animals 1, 2, and 4 mg/kg tramadol (intravenous) increased the apneic threshold (control: 28.3 +/- 4.8 mmHg [mean +/- SD]; after 4 mg/kg: 36.7 +/- 7.1 mmHg; P < 0.05) and decreased the total carbon dioxide sensitivity (control: 109.3 +/- 41.3 ml x min(-1) x mmHg(-1) ) by 31, 59, and 68%, respectively, caused by proportional equal reductions in sensitivities of the peripheral and central chemoreflex loops. Naloxone (0.1 mg/kg, intravenous) completely reversed these effects. In five other cats, 4 mg/kg tramadol caused an approximately 70% ventilatory depression at a fixed Pet co2 of 45 mmHg that was already achieved after 15 min. A third group of five animals received the same dose of tramadol after pretreatment with naloxone. At a fixed Petco of 45 mmHg, naloxone prevented more than 50% of the expected ventilatory depression in these animals. Because naloxone completely reversed the inhibiting effects of tramadol on ventilatory control and it prevented more than 50% of the respiratory depression after a single dose of tramadol, the authors conclude that this analgesic causes respiratory depression that is mainly mediated by opioid receptors.