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Department of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, and Department of Surgery, Johns Hopkins University, Baltimore, Maryland 21224
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Obstructive sleep apnea (OSA) acutely
increases systemic (Psa) and pulmonary (Ppa) arterial pressures and
decreases ventricular stroke volume (SV). In this study,
we used a canine model of OSA (n = 6) to examine the role of
hypoxia and the autonomic nervous system (ANS) in mediating these
cardiovascular responses. Hyperoxia (40% oxygen) completely blocked
any increase in Ppa in response to obstructive apnea but only
attenuated the increase in Psa. In contrast, after blockade of the ANS
(20 mg/kg iv hexamethonium), obstructive apnea produced a decrease in
Psa (
5.9 mmHg; P < 0.05) but no change in Ppa, and the
fall in SV was abolished. Both the fall in Psa and the rise in Ppa that
persisted after ANS blockade were abolished when apneas were induced
during hyperoxia. We conclude that 1) hypoxia can account for
all of the Ppa and the majority of the Psa response to obstructive
apnea, 2) the ANS increases Psa but not Ppa in obstructive
apnea, 3) the local effects of hypoxia associated with
obstructive apnea cause vasodilation in the systemic vasculature and
vasoconstriction in the pulmonary vasculature, and 4) a rise in
Psa acts as an afterload to the heart and decreases SV over the
course of the apnea.
autonomic nervous system; canine; hyperoxia; pulmonary arterial pressure; sleep; systemic arterial pressure; ventricular stroke volume
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SEVERAL MECHANISMS have been proposed to account for the acute pressor responses in the systemic and pulmonary circulations during obstructive sleep apnea (OSA). Hypoxia is thought to play a prominent role in mediating such pressor responses in OSA (10, 17, 33), but clinical studies suggest that administration of supplemental oxygen to OSA patients has little or no effect on attenuating systemic (1) or pulmonary responses (21). Thus a dominant role for hypoxia mediating acute systemic and pulmonary hypertensive responses in OSA has been questioned.
A pressor effect of hypoxia on vascular smooth muscle may occur through two mechanisms. First, chemoreceptors may reflexly activate sympathetic nerves innervating vascular smooth muscle (12, 19, 28). Second, hypoxia may act locally on the vascular smooth muscle to alter its contractility (9, 35). It is currently unclear, however, to what extent the small, transient periods of arterial desaturation in OSA can affect neural and local control of vascular tone in the systemic and pulmonary circulations.
The potential role of neural vs. local effects of hypoxia on the pulmonary arterial response to obstructive apnea has not been studied. Although the pulmonary circulation is considered to have minimal neural regulation (16, 20, 35), recent studies in both animals (34) and OSA patients (24) suggest that sympathetic nerve activity (SNA) to the pulmonary vasculature may increase in response to hypoxia. Hypoxia in the pulmonary vasculature is also known to act directly on smooth muscle to produce vasoconstriction (9, 22, 37). A role for hypoxia acting either neurally or locally remains controversial, however, because supplemental oxygen had minimal effect on reducing acute pulmonary artery pressure (Ppa) swings in OSA patients (21).
We have previously established in the canine model of OSA that the increase in systemic arterial pressure (Psa) in response to an obstructive apnea was completely eliminated by pharmacological blockade of the autonomic nervous system (ANS; Ref. 25). In fact, after blockade of the ANS, the Psa actually fell in the period immediately after the apnea (25). What is currently unknown is the precise role that hypoxia plays during obstructive apnea in the increase in Psa with an intact ANS and the decrease in Psa after blockade of the ANS.
In this study, we examined the neural and local effects of hypoxia on pulmonary and systemic vascular pressures. A canine model of OSA was used to induce apneas without arousal and to examine the effect of normoxia and hyperoxia on cardiovascular responses before and after blockade of the ANS. Specifically, we asked the following questions: 1) Is the increase in Ppa during and immediately after an apnea neurally mediated or due to local hypoxic vasoconstriction? and 2) What is the contribution of hypoxia to the increase in Psa in response to apnea with an intact ANS and the decrease in Psa with the ANS blocked? Furthermore, because ANS blockade removes the increase in systemic vascular pressure, or afterload, in response to an obstructive apnea (25), we examined 3) whether the decrease in stroke volume (SV) during and immediately after an apnea (32) is dependent on an increase in Psa.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Surgical procedures.
Experiments were performed in six mongrel dogs (3 male and 3 female)
weighing 20-25 kg. The animals were pretreated with fentanyl (0.4 mg im) and droperidol (20 mg im) and anesthetized with pentobarbital sodium (30 mg/kg iv), and mechanical ventilation was initiated. A
chronic tracheal stoma was created by removing the ventral portion of
five tracheal rings. Tygon catheters (0.05 in. ID, 0.09 in. OD) were
introduced into the right femoral artery and vein and advanced
rostrally to the thoracic aorta and inferior vena cava, respectively. A
left thoracotomy (fourth interspace) was performed, and electromagnetic
flow probes (Zepeda Instruments, Seattle, WA) were placed around the
ascending aorta in two animals, around the pulmonary artery in two
animals, and around both the ascending aorta and pulmonary artery in
two dogs, as described in the accompanying study (32a). In those
animals with pulmonary artery flow probes, Tygon catheters (0.05 in.
ID, 0.09 in. OD) were also placed in the pulmonary artery and left
atrium for monitoring vascular pressures. A balloon catheter was
anchored to the inside of the chest wall at the level of the fourth
interspace on the right side of the chest to estimate pleural pressure
(Ppl). The chest was then closed, and negative intrapleural pressure
was established with a chest tube to completely reinflate the lungs.
The chest tube was removed, and spontaneous ventilation was allowed to
resume. All catheters and electrical leads were tunneled
subcutaneously, exteriorized between the scapulae, and protected in the
pocket of a jacket. Polysomnographic leads for measurement of
electroencephalographic (EEG) and nuchal electromyographic (EMG)
activity were attached with needle electrodes only during data
collection periods. Patency and sterility of the vascular catheters
were maintained by filling them with a mixture of heparin (1,000 U/ml)
and penicillin G potassium (20,000 U/ml). All catheters were flushed
and had the dead space fluid replaced at a minimum of every 72 h. The
animals were allowed at least 2 wk to recover from surgery, during
which time they were monitored daily and acclimated to the laboratory
environment. All animals were treated with a broad-spectrum antibiotic
(30 mg · kg
1 · day1
trimethoprim/sulfadiazine), beginning at the time of surgery and
continuing for 7-10 days postoperatively. The study was approved by the Johns Hopkins University Animal Use and Care Committee and
complied with the American Physiological Society guidelines.
Apparatus and methods of measurement. A custom-designed endotracheal tube was used to control airway patency, measure arterial Hb saturation (averaged every 1 s; minimum detectable change of 1%), and allow sampling of end-tidal carbon dioxide and measurement of tracheal pressure (Ptr) from side ports (27). After hexamethonium administration, dilation of the trachea precluded reliable contact of the oximeter probe with the mucosal lining and prevented measurement of arterial Hb saturation, as previously discussed (25). The resistance of the endotracheal tube and the time constants for obstructing and restoring airway patency have been described previously (27). The connections from the endotracheal tube, the polysomnographic extension leads, and the vascular lines were placed in a 40-in.-long flexible tube that attached to the back of the animal's jacket.
The animals slept in a specially constructed box with a clear Plexiglas front panel that could be monitored from an adjacent room with a shortwave closed-circuit television. The flexible tube containing the recording wires and catheters exited through a hole in the top of the sleep box and passed under a communicating door and attached to the recording equipment in the adjacent room. Intravascular and airway pressures measurements were made with pressure transducers (Cobe, Lakewood, CO) zeroed at midthoracic level with the animal lying prone. Calibrations were checked at 30-min intervals throughout experiments. A pen recorder (Grass Instruments, Quincy, MA) was used to record EEG and EMG activity and Psa, Ppa, left atrial pressure (Pla), Ppl, and Ptr traces. The SV of the left and right ventricle were measured with a model SWF-5RD electromagnetic flowmeter (Zepeda Instruments). A Nellcor N-200 pulse oximeter (Haywood, CA) measured arterial Hb saturation and a Beckman analyzer (Anaheim, CA) sampled end-tidal carbon dioxide. Both instruments were connected to the pen recorder. Data from the pen recorder were sampled at 300 Hz and converted to digital format (DI-200 data acquisition board; Dataq Instruments, Akron, OH) and acquired to optical disk for storage with Windaq/200 acquisition software (Dataq Instruments). The velocity signal from the electromagnetic flow probe was digitally integrated to determine SV. Transmural Ppa (Ppa Ppl; Ppa,tm) and transmural Pla (Pla Ppl; Pla,tm) were
calculated from the digital waveforms for analysis during periods of
obstructive apnea as detailed under Data analyses.
Experimental protocol. Each dog (n = 6) was subjected to a period of 24-h sleep deprivation before each experiment, as previously described (26, 27, 32), and each experiment was conducted between 1400 and 2000. We conducted a series of tracheal airway obstructions without arousal during non-rapid-eye-movement (NREM) sleep before and after pharmacological blockade of the ANS with hexamethonium (intravenous infusion of 20 mg/kg). The efficacy of the blockade was verified by the absence of a reflex bradycardia in response to phenylephrine (100 µg iv bolus as previously reported; Ref. 25). The duration of all apneas was controlled such that restoration of airway patency was not associated with arousal based on EEG and EMG criteria as previously described (25, 32a). All data were collected within 60 min before and 60 min after administration of hexamethonium.
In a second set of experiments, apneas were induced without arousal in five dogs during NREM sleep while the animals were breathing either room air or hyperoxia (40% O2 in nitrogen). As above, all animals were sleep deprived for 24 h before the experiment. In a third series of experiments, apneas were induced without arousal in two of the six animals during NREM after hexamethonium administration (20 mg/kg) while the animals breathed either room air or hyperoxia (40% O2 in nitrogen). As above, all animals were sleep deprived for 24 h before the experiment, and the efficacy of blockade was checked and all data were collected within 60 min after hexamethonium administration.Data analyses. Sleep/wake states were characterized as either awake (low-amplitude and high-frequency central EEG activity and high-frequency nuchal EMG activity), NREM sleep (high-amplitude and low-frequency central EEG activity and decreased nuchal EMG activity compared with awake), and rapid-eye-movement (REM) sleep (low-amplitude and high-frequency central EEG activity, similar to awake, and reduced nuchal EMG activity compared with awake and NREM sleep), as previously described for the canine model (27). Arousal was classified by the changes in EEG and EMG activity at apnea termination according American Sleep Disorders Association criteria (2).
Apnea duration was defined as the time from onset of an apnea to the nadir of the last inspiratory effort during the apnea. Data were only analyzed for obstructive apneas induced in NREM sleep that did not result in arousal. Apneas before and after hexamethonium administration were matched for duration and number of respiratory efforts. [Note: arterial oxyhemoglobin saturation could not be determined in our canine model after hexamethonium administration as previously described (25)]. Ventricular output was calculated as SV × heart rate (HR). There were no differences between left and right ventricular SV as previously described (32), so data were then pooled to provide a single value for ventricular SV. The following definitions and criteria were used in the measurement of preapnea, end-apnea, and postapnea values for Psa, Ppa,tm, Pla,tm, and HR: Preapnea is the three respiratory cycles immediately before apnea, end-apnea is the last two "inspiratory and expiratory cycles" of the apnea, and postapnea is the first three respiratory cycles after the restoration of airway patency. Before data analyses, the vascular pressure signals were filtered digitally (Windaq, filter factor 100, Dataq Instruments) to provide a mean pressure. The filtered traces were then used to assess the mean vascular pressures at various points throughout the apnea cycle. At preapnea, vascular pressures were calculated as the maximum expiratory level averaged for the three respiratory cycles during this period. At end-apnea and postapnea, vascular pressures were calculated as the maximum expiratory value during each period. The HR was measured from the pulsatile arterial blood pressure trace by counting the number of systolic peaks over each period. A summary of the apnea characteristics and dogs used for each analysis is presented in Tables 1-3. For each animal, the values for pre-, end-, and postapnea were averaged over three to five apneas. The averaged data from each animal were then pooled across all the animals and analyzed by paired t-test. Differences were considered significant if P < 0.05. Data were analyzed using Crunch 4 (Crunch Software, Oakland, CA) and are reported as means ± SE, unless otherwise stated.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ANS blockade and normoxic breathing.
The respiratory characteristics of obstructive apneas induced without
arousal during NREM sleep are shown in Table
1 before (control) and after ANS blockade
(hexamethonium). Figure 1 is a sample trace
from one animal showing the cardiovascular response to obstructive
apneas during NREM sleep before (control, A) and after ANS
blockade (hexamethonium, B). Before ANS blockade, obstructive apneas during NREM sleep increased Psa by ~15 mmHg and Ppa by ~5
mmHg from preapnea to postapnea. After ANS blockade, obstructive apneas
produced increases in Ppa comparable to those seen before blockade. In
contrast, in the systemic circulation, Psa no longer increased during
obstructive apnea but rather decreased noticeably from preapnea to
postapnea.
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Hyperoxic breathing.
The respiratory characteristics of obstructive apneas induced without
arousal during normoxic and hyperoxic breathing in animals with an
intact ANS are shown in Table 2. Figure
4 shows that inducing obstructive apneas
during hyperoxia significantly (P < 0.025) blunted the
increase in Psa from pre- to postapnea compared with apneas induced
while animals were breathing room air (normoxia). However, Psa still
increased significantly from pre- to postapnea by 6.7 ± 2.0 mmHg in
the presence of hyperoxia. In contrast, hyperoxia completely abolished
any increase in Ppa,tm from pre- to postapnea.
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ANS blockade and hyperoxic breathing.
The respiratory characteristics of obstructive apneas induced without
arousal after ANS blockade during normoxic and hyperoxic breathing are
shown in Table 3. Figure
5 shows a sample trace of obstructive
apneas from one animal after ANS blockade breathing either room air
(normoxia, A) or 40% oxygen (hyperoxia, B). After ANS
blockade and during normoxic breathing, inducing obstructive apneas
produced an increase in Ppa and a decrease in Psa as described above
(Figs. 1 and 2). However, these changes in vascular pressures during
obstructive apnea after ANS blockade were eliminated during hyperoxic
breathing. Averaged Psa and Ppa,tm responses from each of two dogs
after ANS blockade when obstructive apneas were induced during normoxia
and hyperoxia are shown in Figs. 6 and
7. From pre- to postapnea, the Psa (Fig.
6) decreased in both animals during normoxia (12.6 ± 2.3 mmHg
in dog 1 and 16.8 ± 3.8 in dog 2; means ± SD). During hyperoxia, Psa did not change in either animal from pre- to
postapnea (0.5 ± 2.0 mmHg in dog 1 and
1.3 ± 2.7 in dog 2; mean ± SD). From pre-
to postapnea, the Ppa,tm (Fig. 7) increased in both animals during
normoxia (3.2 ± 0.5 mmHg in dog 1 and 1.7 ± 0.9 mmHg in
dog 2; means ± SD). During hyperoxia, Ppa,tm did not change
in either animal from pre- to postapnea (0.0 ± 0.5 mmHg in dog
1 and 0.3 ± 0.2 in dog 2; means ± SD).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study in a canine model of OSA demonstrates an important role for hypoxia in modulating vascular tone in the systemic and pulmonary circulations during OSA. We show that there was no detectable neural component in the pulmonary hypertensive response to airway obstruction (Figs. 1 and 2). In fact, the data demonstrate that local hypoxic vasoconstriction was responsible for all of the increase in Ppa during obstructive apnea (Figs. 4, 5, and 7). With regard to the systemic circulation, we confirmed our previous finding (25) that in OSA the acute hypertensive response is dependent on an intact ANS and that after ANS blockade Psa falls in response to an obstructive apnea (Figs. 1 and 2). Thus a neurally mediated increase in Psa in obstructive apnea occurs against a background of concomitant vasodilation. The present study extends this previous work in two ways: 1) by demonstrating that the neurally mediated increase in Psa in response to an obstructive apnea in animals with an intact ANS is dependent predominantly, but not exclusively, on hypoxia (Fig. 4) and 2) by showing that the vasodilation of the systemic vasculature after ANS blockade is due to hypoxia (Figs. 6 and 7). Finally, we show that the fall in SV over the course of an obstructive apnea is afterload induced, because SV no longer decreases in the absence of a rise in Psa after ANS blockade (Fig. 3). The relative contributions of neural and local effects of hypoxia on the pulmonary and systemic circulations may have important implications in terms of cardiovascular risk and treatment in OSA patients. In the discussion that follows, we examine the neural and local effects of hypoxia in OSA and the implications of this work for patients with this disorder.
Neural effect of hypoxia. The present study demonstrates the central role that the ANS plays in the acute systemic blood pressure increases in OSA. Previous work in humans and animal models have shown that it is hypoxia that provides this stimulus to the ANS to increase systemic blood pressure during apnea (3, 11, 12, 17, 23, 28, 36). For example, we have previously demonstrated that hypoxic stimulation of the carotid chemoreceptors can account for at least 80% of the increase in renal sympathetic nerve activity (SNA) and all of the increase in Psa that occurs in response to apnea in anesthetized cats (28). However, data from the present study suggest that although hypoxia may be the main factor, it is not the only factor reflexly increasing Psa during obstructive apnea. Before blockade of the ANS, Psa still increased significantly (6.7 ± 2.0 mmHg) in the presence of hyperoxia. Given that ANS blockade completely eliminated any systemic blood pressure response to apnea, this remaining 6.7 mmHg response during hyperoxia must be reflex in nature and independent of hypoxia. According to the theoretical schema of Chen et al. (6), other possible reflex pathways include loss of mechanoreceptor activity from the lung, chest, and heart and increased central sympathetic activity from the hypercapnia. Thus hypoxia is the dominant, but not exclusive, factor reflexly increasing Psa during obstructive apnea.
A potential consequence of the neurally mediated rise in Psa during obstructive apnea is an afterload to the heart that increases throughout the apneic cycle. Our data demonstrate that, during apneas without arousal, the increase in Psa is associated with an acute decrease in SV and no change in HR. This decrease in SV is consistent with an acute increase in left ventricular afterload. An increase in left ventricular afterload may contribute to the decrease in SV previously reported during obstructive apneas in human OSA (4, 14, 15, 38), in the canine model (32), and in a sedated pig model (5). In the present study, the use of hexamethonium to induce ANS blockade enabled us to produce obstructive apneas in the absence of an increase in afterload (no increase in Psa with constant HR). Under these conditions, there was no longer a fall in SV during obstructive apnea. Thus we conclude that sympathetically mediated acute constriction of the systemic vasculature acts as an afterload that reduces SV over the course of an obstructive apnea. It is well recognized that obstructive apneas also cause increases in Ppa (7, 21, 31, 32). It is currently unclear what role, if any, the ANS plays in mediating the increase in Ppa during obstructive apnea. Although recent studies have suggested that the ANS output to the pulmonary vasculature may increase in response to hypoxia (24, 34), in the present study we show that the increase in Ppa during obstructive apnea is not affected by blockade of the ANS. Therefore, in our canine model, there is no neural component to the transient surges in Ppa in OSA. An inability of the ANS to modulate Ppa was also seen in a previous study by our group examining the changes in pulmonary vascular resistance as a function of sleep state during normal, unobstructed breathing (32). Thus the pulmonary vasculature is unresponsive to activation of the ANS during obstructive apnea in the dog. The conclusions reached in the present study regarding the role of the ANS in acute fluctuations in Ppa and Psa are consistent with observations in humans with an impaired ANS. Anecdotal observations in OSA patients with Shy-Drager syndrome suggest that increases in Psa during obstructive apneas are dependent on an intact ANS (8). In contrast, the acute surges in Ppa during OSA remained present in Shy-Drager patients. Furthermore, increases in Psa and muscle SNA during simulated apneas in awake, normal humans were abolished by ganglionic blockade (18). These human data are consistent with the results of the present study, indicating that acute surges in Psa, but not Ppa, are mediated through the ANS.Local effects of hypoxia. In the systemic circulation, blood pressure actually fell in response to an obstructive apnea after blockade of the ANS. This finding indicated that, in the absence of autonomic neural pathways, some factor associated with the obstructive apnea dilated the systemic vascular bed. Because the postapnea vasodilation after ANS blockade was abolished by the application of hyperoxia, we conclude that, in our canine model of OSA, hypoxia has a local vasodilating effect on the systemic vasculature. In a sedated pig model of obstructive apnea, ANS blockade reduced the blood pressure response to apnea (6) but did not cause a fall below baseline as seen in the canine model. Interestingly, after the addition of hyperoxia, blood pressure fell in response to apnea in the ANS-blocked pig, suggesting that the local effects of hypoxia on the systemic circulation during apnea appear to be vasoconstrictive, whereas in the canine model of OSA the local effects of hypoxia are vasodilating. Whether such a disparity in the local effects of hypoxia is due to species differences, the effects of sedation vs. sleep, or other factors remains unanswered.
The predominant local effect of hypoxia in the pulmonary circulation is vasoconstrictive in nature (9, 22, 37). In the present study we show that hypoxia is the only mechanism increasing Ppa in obstructive apnea. Moreover, this acute hypertensive response is entirely due to local hypoxic pulmonary vasoconstriction. What is perhaps surprising about this result is that the very brief duration of apnea can induce such a brisk hypoxic pulmonary vasoconstrictor response. Thus a very low threshold may exist for the hypoxic stimulus from an obstructive apnea to produce acute pulmonary hypertension. A low threshold for hypoxic pulmonary vasoconstriction in OSA may explain the ineffectiveness of supplemental oxygen at relieving acute pulmonary hypertensive episodes reported in six OSA patients (21), in whom the administration of 4-6 l/min of nasal oxygen did not abolish the acute fluctuations in transmural Ppa during OSA. However, the data show that the degree of supplemental oxygen did not completely eliminate arterial oxygen desaturation during apneas as there was a demonstrable fall in arterial Hb saturation, the average low of which reached 91% in two patients. Thus an hypoxic stimulus persisted in these patients, and the magnitude was comparable to the hypoxic stimulus that produced increases in transmural Ppa in our canine model (Table 1). Therefore, human and animal data suggest that very small, transient periods of hypoxia with small arterial Hb desaturation during obstructive apnea may cause significant increases in Ppa. On the basis of our canine model, we predict that OSA patients may experience significant relief from nighttime acute pulmonary hypertensive episodes if sufficient supplemental oxygen can be delivered to raise alveolar oxygen tension. Our data from the present study in combination with the accompanying study (32a) indicate that hypoxia is the predominant stimulus to acute pulmonary hypertension in obstructive apnea independent of influences from arousal, sleep state, or CO2. As such, treatment with hyperoxia may be particularly important in OSA patients with preexisting conditions (13, 29). For example, acute nighttime elevations in Ppa may put OSA patients with primary pulmonary hypertension, right heart failure, or chronic hypoxemia at increased cardiovascular risk (30). Thus patients who cannot wear continuous positive applied pressure masks or adhere to other treatments for OSA might benefit from relief of the hypoxemia. In summary, hypoxia plays a key role in the acute systemic and Ppa fluctuations in OSA. In the systemic circulation, hypoxia associated with periodic airway obstruction reflexly activates the ANS to produce vasoconstriction but acts against a background of locally mediated vasodilation. The resultant increase in Psa acts as an afterload to the heart and decreases SV over the course of an obstructive apnea. In the pulmonary circulation, the transient hypoxic episodes associated with OSA produce a marked local hypoxic vasoconstrictor response. These results indicate that administration of hyperoxia could alleviate nighttime fluctuations in Ppa during OSA and help protect those patients with coexisting morbidity of the right side of the circulation.| |
ACKNOWLEDGEMENTS |
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We acknowledge Nellcor (Haywood, CA) for time in discussing the measurement of arterial Hb saturation and the generous loan of the oximetry equipment.
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FOOTNOTES |
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This study was funded by grants from the National Heart, Lung, and Blood Institute (HL-51292), the American Heart Association, and Deutsche Forschungsgemeinschaft (SCH543/1-1).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: C. P. O'Donnell, Rm. 4B63, Johns Hopkins Asthma and Allergy Ctr., 5501 Hopkins Bayview Cir., Baltimore, MD 21224 (E-mail: codonnel{at}welch.jhu.edu).
Received 3 March 1999; accepted in final form 8 November 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and after
hexamethonium blockade of the ANS (
). Pre, 3 respiratory cycles
immediately before apnea; End, last 2 "inspiratory and expiratory
cycles" of apnea; Post, first 3 respiratory cycles after restoration
of airway patency. Pooled data include only apneas that were terminated
without arousal during NREM sleep. Differences from preapnea to
postapnea between control and hexamethonium conditions were determined
by paired t-test (two-tailed).
