The Role of Vascular Tone in the Control of Upper Airway Collapsibility1-3
MICHAEL J. WASICKO, DOUGLAS A. HUTT, RICHARD A. PARISI, JUDITH A. NEUBAUER, REUBEN MEZRICH, and NORMAN H. EDELMAN With the technical assistance of Judith Gronlund-Jacob and Donna Chigi
Introduction
During normal eupneic breathing, the negative pressure generated by the thoracic pump muscles favors collapse of the upper airway. The principal defense of upper airway patency has been thought to be activation of upper airway skeletal muscles. However, nonmuscular mechanical properties of upper airway components such as connective tissue, blood vessels, and mucosa must also be important. Knowledge of mechanisms that influence upper airway collapsibility 1S important in understanding the pathogenesis of obstructive sleep apnea since this condition is characterized by increased pharyngeal collapsibility during sleep(1, 2). The structural and functional basis of this disorder is still unclear. A number of investigators have shown the importance of skeletal muscles in controlling pharyngeal patency. Activation of pharyngeal dilator muscles, such as the genioglossus, decreases upper airway resistance and collapsibility (1, 3). Additionally, caudal traction of the trachea by the cervical strap muscles can also reduce upper airway resistance (4). The role of nonmuscular factors in the active control of airway patency is less well understood. However, it has been suggested that these factors may also modulate airway collapse. Olson and Strohl (5) have shown in anesthetized rabbits that paralysis of skeletal muscles does not change upper airway closing or opening pressures during ventilation with 100070 O 2 and does not abolish the augmentation by hypercapnia of the upper airway's resistance to collapse. These investigators concluded that upper airway dilator muscle contraction is not essential to the ability of the pharynx to resist collapse and that nonmuscular factors might play an important role. One nonmuscular factor subject to active central neural control is vasomotor tone of the upper airway soft tissues. In
SUMMARY Upper airway collapsibility may be influenced by both muscular and nonmuscular factors. Because mucosal blood volume (and therefore vascular tone) is an important determinant of nasal airway patency, vascular tone may be an important nonmuscular determinant of pharyngeal collapsibility. This hypothesis was tested in two experimental models. First, upper airway closing (CP) and opening (OP) pressures and static compliance were measured in nine anesthetized, sinoaortic-denervated, paralyzed cats with isolated upper airways. Vascular tone was decreased with either papaverine or sodium nitroprusside (NTP), and increased with phenylephrine (PE), whereas blood pressure and end-tidal CO2 were maintained constant. Vasodilation increased CP (control = -10.4 ± 1.3, NTP = -7.3 ± 1.2 cm H20; P < 0.05) and OP (control = -7.9 ± 1.5, NTP = -3.3 ± 1.8 cm H20; p < 0.05). In contrast, vasoconstriction tended to decrease CP (control = -10.7 ± 1.5, PE = -11.7 ± 1.4 cm H20; p < 0.09) and OP (control = -8.1 ± 1.2, PE = -9.9 ± 1.9 cm H20; P < 0.1). Thus, vasodilation increased and vasoconstriction tended to decrease upper airway collapsibility. Upper airway static compliance was unchanged during either drug infusion. In order to assess changes in pharyngeal cross-sectional area (CSA)that occurred during vasodilation, magnetic resonance imaging was utilized in seven cats. During vasodilation with NTP, pharyngeal CSA was reduced from 0.44 ± 0.10 to 0.30 ± 0.09 em" (p < 0.05), and pharyngeal volume was reduced from 15.3 ± 2.4 to 13.9 ± 2.7 ern" (p < 0.05). The decrease in pharyngeal caliber was largely attributable to increased thickness of the posterolateral pharyngeal mucosa. Vascular tone appears to be an important nonmuscular determinant of upper airway collapsibility. AM REV RESPIR DIS 1990; 141:1569-1577
the nose, vascular tone and mucosal blood volume are dynamically controlled and are important determinants of nasal airway patency. Nasal resistance decreases when vascular tone is increased pharmacologically (6) or when sympathetic activity is increased with either hypercapnia (7) or application of the excitatory amino acid N-methyl-n-aspartate to the ventral surface of the medulla (8). Because mucosal blood volume is important in regulating nasal airway patency, we hypothesized that control of pharyngeal mucosal vascular tone is an important nonmuscular determinant of pharyngeal collapsibility. Specifically, we hypothesized that decreased vascular tone, and the subsequent increased mucosal blood volume, would result in a more collapsible upper airway. We tested this hypothesis in anesthetized, paralyzed supine cats using two experimental paradigms. First, the range of the effect of vascular tone on pharyngeal collapsibility was determined by measuring upper airway closing and opening pressures and static compliance while maxi-
mal vasodilation and vasoconstncnon wereinduced pharmacologically. Second, magnetic resonance imaging (MRI) was used to observe the changes in upper airway anatomy that occurred during changes in vascular tone. Methods General Preparation Collapsing pressures. Nine adult cats weigh(Received in original form August 7, 1989and in revised form December 4, 1989) 1 From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, and the Department of Radiology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey. 2 Supported by Research Grant No. HL-01549 and HL-16022 and Training Grant No. HL-07467 from the National Heart, Lung, and Blood Institute, and by Fellowship Award No. 88-049 from the American Heart Association/New Jersey Affiliate. 3 Correspondence and requests for reprints should be addressed to Richard A. Parisi, M.D., Division of Pulmonary and Critical Care Medicine, UMDNJRobert Wood Johnson Medical School, One Robert Wood Johnson Place-CN 19, New Brunswick, NJ 08903-0019.
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WASICKO, HUTT, PARISI, NEUBAUER, MEZRICH, AND EDELMAN
ing between 2.5 and 4 kg were preanesthetized paralyzed, and mechanically ventilated as desure generation at the tracheal catheter within a wide range. intramuscularly with a mixture of ketamine scribed above. A femoral artery and both femHCI 00 mg/kg) and acepromazine (1.1 mg/ oral veins were cannulated for measurement Upper airway static compliance was meakg). Anesthesia was subsequently maintained of arterial blood gas tensions and pH and adsured by changing the volume of the upper intravenously with alpha-chloralose (20 to 40 ministration of the vasodilating agent sodiairway by known amounts above or below its um nitroprusside as well as anesthetics. mg/kg, supplemented regularly). Rectal temresting volume and recording the concomiperature was monitored and maintained at The carotid sinus nerves and vagi were left tant change in either nasal or tracheal pres38° C with a heating pad. Brachial arterial intact, and the cervical sympathetic nerves sure. The change in airway volume was plotted against the change in airway pressure. were sectioned bilaterally in the neck. Presand venous catheters were inserted for meaVascular tone was altered pharmacologisurement of blood pressure (Statham 23Db ervation of baroreflexes allowed the animal cally with vasoconstriction produced by inpressure transducer; Statham Instruments, to maintain a constant arterial blood presfusion of phenylephrine and vasodilation proOxnard, CA) and administration of anesthetics. sure during the infusion of sodium nitroprusA midline abdominal incision was perside, whereas sectioning of the cervical symduced by infusion of either papaverine (n = formed, and the abdominal aorta and inferipathetic nerves removed neurogenic vasomo2) or sodium nitroprusside (n = 7). The drugs tor influences on the upper airway. The tongue or vena cava were isolated and ligated just were slowly and continuously infused intrawas pulled anteriorly and secured to the low- venously with a monostaltic pump (Buchler proximal to the bifurcation of the femoral arteries. A low resistance, high capacitance res- er lip to prevent prolapse into the airway. The Instruments, Fort Lee, NJ) such that the doses ervoir containing isosmotic mannitol was conanimals were then placed in a semicylindrical were approximately 10 ug/kg/rnin for phennected to the descending aorta, and its height holder in the supine position with the neck ylephrine, and 20 ug/kg/min for sodium was adjusted to maintain systemic arterial slightly extended. In two cats the upper airnitroprusside. Papaverine was given at a conblood pressure constant at a mean level of way was isolated and sealed, as described stant dose of2 rug/kg at a rate of 0.1 mllmin. approximately 90 mm Hg. Phenylephrine and sodium nitroprusside were above, before MRI. This was done to identiThe trachea was isolated low in the neck fy the site of collapse during the generation infused to a steady state with respect to inand sectioned approximately I em below the of a negative pressure. travascular volume as estimated by the height larynx. Care was taken to ensure that the upof the aortic reservoir column (mean ± SE Protocol per airway muscles remained intact. A mark total doses: phenylephrine = 288 ± 29Ilg/kg; was made at the site of sectioning so that the sodium nitroprusside = 169 ± 56 ug/kg), Collapsing pressures. In order to prevent hyptrachea and the upper airway muscles could oxia, the animals were ventilated with 40% Upper airway closing and opening pressures be extended to their natural positions during O 2 , The cats were in the supine position, and and static compliance were measured before, the experimental procedure. The caudal tracare was taken to maintain a constant amount during, and 30 to 60 min after discontinuing chea was cannulated for mechanical ventilaof neck flexion for the duration of the ex- the infusion of either the vasodilating or tion. The cats were paralyzed (gallamine triperiment; typically, the head was at a 20 to vasoconstricting agent; both vasodilation and ethiodide) and mechanically ventilated while vasoconstriction were tested in each animal 40-degree angle with the spine. end-tidal CO 2 was maintained constant at 4.5 in a random order. The closing and opening The method of determining upper airway to 5.0070 by adjustment of the ventilator freclosing and opening pressures in this isolated pressures obtained under each experimental quency. The vagus nerves were sectioned system is illustrated in figure 1. This shows condition were the average of five determibilaterally in the neck. The carotid sinus nerves simultaneous recordings of nasal and trachenations. Upper airway static compliance was were also sectioned bilaterally through small al pressures while negative pressure was genermeasured only after an effect of the vasoacincisions on the ventrolateral surface of the ated at the tracheal catheter. When nasal prestive drug was observed. neck in the region of the carotid sinus. This Upper airway imaging. A-0.6 Tesla magsure was equal to tracheal pressure, upper airapproach was chosen to minimize disruption way patency was inferred. The pressure at net (Teslacon, Technicare, Solon, OH) was of the upper airway. used for these experiments. A human neck which there was discordance between the reThe upper airway was then isolated by the cordings was defined as the upper airway closcoil was positioned around the animal to almethods previously described by Brouillette ing pressure. As tracheal pressure was returned low imaging of the head and neck region. The and Thach (3) and Strohl and Fouke (9). The toward atmospheric pressure, nasal pressure animal was centered visually with the aid of rostral end of the sectioned trachea was caninitially remained constant and then abruptlaser cross-hairs, and moved into the MRI apnulated with a large-bore catheter positioned ly increased along with tracheal pressure, inparatus. The animals remained in this posicaudal to the vocal cords. The catheter was dicating the airway had become patent. The tion for the duration of the experiment. connected to a lO-ml syringe through which tracheal pressure at which airway patency was In this study, magnetic resonance imaging pressure could be generated. A second cathereestablished was defined as the upper airwas performed using the spin echo technique, ter was inserted into the nares, and the tip way opening pressure. Both closing and opena powerful method that utilizes differences was positioned approximately 0.5 ern anteriing pressures were found to be reproducible in the dynamic behavior of hydrogen nuclei or to the junction of the hard and soft palate. under each experimental condition, and were in a magnetic field to perturbation by a series The tongue was pulled an teriorly, and the found to be independent of the rate of presof radio frequency pulses. The information buccal cavity and nose were sealed with glazing compound and cyano-acrylate to create a closed sytem. The upper airway was con5 sidered sealed if a pressure of ± 10 cm H 2 0 could be held for 20 to 30 s. Care was taken 0 during the preparation not to disrupt arterial aN Fig. 1. Technique for determining airsupply to the pharynx or to physically ma- :r: -5 E way closing and opening pressures in nipulate the pharyngeal mucosa. Both the na- ~ PNASAL 7 + - OPENING PRE5SUllE the sealed, isolated upper airway. Simulw -10 sal and tracheal catheters were connected to a::: Q.OSINCPRESSURE --+ •••,.--•• ------ •• - - - .1 taneous nasal and tracheal pressures ::> differential pressure transducers (Validyne l/) l/) are shown while a negative pressure w -15 Corp., Northridge, CA) referenced to atD::: was generated and released at the traa.. mospheric pressure. cheal catheter. See text for details. -20 Upper airway imaging. The size constraints of the MRI apparatus required changes in the -25 0 10 15 above experimental model. Seven cats weigh5 20 25 ing between 2.5 and 3 kg were anesthetized, TIME (SEC)
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VASCULAR TONE AND UPPER AIRWAY COLLAPSIBILITY
is then used to generate images of graded intensity noninvasively and without ionizing radiation. Relative dependence of image intensity on either of two time constants, Tl and T2, can be controlled by varying two pulse sequence parameters, repetition time (T R) and echo time (T d. In this study, both Tlweighted (T R = 500 ms, T E = 33 ms) and T2-weighted (TR = 2,000 ms, T E = 110ms) scans were performed. Tl-weighted images, which provide better overall contrast, were used to define the anatomy of the upper airway.On T2-weighted images, intensity is most closely related to water content. These images were therefore used to assess relative changes in interstitial tissue water or blood. Both sagittal and transverse views of the upper airway were used, and the sequence of scanning was as follows. First, Tl-weighted sagittal views of the upper airway were used to define the region in which transverse sections would be taken. This region started at the junction of the hard and soft palate and continued caudally to a region below the epiglottis. Serial, contiguous Tl-weighted transverse sections (4 mm thick) were then made in this region. Transverse views allowed for the calculation of pharyngeal cross-sectional area and volume. Noncontiguous T2-weighted transverse scans (6 mm thick with 1 mnvspacing) were then obtained. Upper airway anatomy and mucosal water content were examined under control conditions and after vasodilation with continuous intravenous infusion of sodium nitroprusside. Because there was no available index to assure that a steady-state effect had been achieved with sodium nitroprusside, the animals were given the same total dose found to maximally decrease airway closing pressure in the first series of studies (200 ug/kg). In two cats, the site of airway collapse during application of negative pressure was determined by utilizing sagittal TI images. In these cats, the upper airway was isolated and sealed as described in the first protocol. The airway was collapsed by generating a negative pressure at the tracheal catheter. Because pressure was not recorded, the airway was assumed to be collapsed if air could no longer be removed through the tracheal catheter.
Data Analysis In the experiments using the sealed upper airway model, it was found that under any experimental condition significant interanimal differences in airway closing and opening pressures were present, and the data were determined to be nonparametric. To account for this, Friedman's rank sum test (10) was used to compare control closing and opening pressures to both those obtained during the drug infusion and postdrug infusion. A level of 0.05 was considered to be significant. Changes in upper airway static compliance during the infusion of the vasoactive drug were assessed by inspection of the volume-pressure relationships. . In the MRI studies, pharyngeal cross-sectional area was plotted as a function of the
TABLE 1 ARTERIAL BLOOD PRESSURE AND END-TIDAL CO2 DURING VASODILATION AND VASOCONSTRICTION
Condition Control (vasodilation runs) Vasodilation Control (vasoconstriction runs) Vasoconstriction Definition of abbreviations: PAP
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Dose
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2 mg/kg 169 ± 56 Ilg/kg
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distance caudal from the junction of the hard and soft palate for both control and vasodilated conditions. Because the transverse sections used in this study were of a constant thickness, area was measured every 4 mm. At each point the control area was compared with the area obtained during vasodilation via paired t-test. Additionally, the volume of the pharyngeal airway was calculated by integrating the area-distance function. The volumes calculated during control and vasodilated conditions were compared using the paired t-test. A levelof 0.05 was considered significant. T2weighted scans were inspected for changes in water content in the pharyngeal mucosa. Results
Collapsing Pressures The values of end-tidal CO 2 and blood pressure are shown in table 1 for control conditions and during vasodilation and vasoconstriction. Note that two sets of control measurements are shown - one obtained before vasodilation and the other before vasoconstriction. Neither endtidal CO 2 nor blood pressure changed significantly during vasodilation or vasoconstriction. The mean airway closing and opening pressures obtained before, during, and after vasodilation and vasoconstriction are shown in figure 2. Control closing pressures were similar prior to vasodilation (-lOA ± 1.3 em H 20; range, -4.0 to -15.1 em H 20) and vasoconstriction (-10.7 ± 1.5 ern H 20; range, - 5.3 to -18.9 em H 20). Control opening pres-
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5.0 ± 0.1 5.3 ± 0.2
93.2 ± 4.3 91.7 ± 3.7
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Fig. 2. The effect of vasodilation (left panel) and vasoconstriction (right panel) on closing and opening pressures (n = 9). Pressures are shown for control, drug infusion, and 30 min after drug infusion. Note that vasodilation resulted in an airway that was more collapsible, whereas vasoconstriction resulted in an airway that was less collapsible. Asterisks indicate p < 0.05.
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sures were -7.9 ± 1.5 em H 20 (range, - 2.3 to -12.9 em H 20) before vasodilation and - 8.1 ± 1.2 em H 20 (range, - 2.1 to -12.9 cm H 20) before vasoconstriction. Control measurements of each parameter repeated after withdrawal of either treatment were not different from the initial baseline values. During vasodilation, both closing and opening pressures wereless negative. Closing pressure increased to - 7.3 ± 1.2 em H 20 and opening pressure to - 3.3 ± 1.8 cm H 20 during infusion of sodium nitroprusside (n = 7) or papaverine (n = 2). All nine animals followed this trend during vasodilation (p < 0.01). In two animals, airway opening pressure increased dramatically to supra-atmospheric levels: -1.9 to + 2.8 ern H 20 in one, and - 8.8 to + 5.7 em H 20 in the other. In contrast, during vasoconstriction, closing pressure tended to become more negative. Closing pressure decreased to -11.7 ± 1.4 em H 20 during infusion of phenylephrine. This difference was not statistically different from control values (p < 0.09) because five of nine animals had no response to vasoconstriction despite large doses of phenylephrine. Opening pressure during vasoconstriction was - 9.9 ± 1.9 cm H 20, and although this tended to be more negative than the control values, the difference was not statistically significant. The minimal effect of phenylephrine on airway closing and opening pressures
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WASICKO. HUTT, PARISI, NEUBAUER, MEZRICH, AND EDELMAN
suggested that the mucosal vessels were already in a relatively vasoconstricted state. This was likely since we have found in other experiments using similarly prepared (anesthetized, barodenervated, vagotomized) cats that systemic vascular resistance is quite high (11). Thus, infusion of the vasoconstrictive agent phenylephrine could have had little additional effect on the vasculature. To test this, phenylephrine was infused immediately after closing and opening pressures had been increased by vasodilation with sodium nitroprusside in one cat. Because the effect of this vasodilating agent on airway closing and opening pressure was found to last 30 to 60 min after the infusion was discontinued, an immediate and opposite effect (within a few minutes) of phenylephrine would suggest that vasoconstriction with this agent does not have a direct effect on pharyngeal collapsibility. In this animal, a dose of 50 ug/kg sodium nitroprusside increased closing pressure from -10.4 to - 3.2 cm H 2 0 . Infusion of phenylephrine immediately after the removal of sodium nitroprusside decreased closing pressure to -12.0 em H 2 0 within 3.5 min. Therefore, both vasodilation and vasoconstriction produced substantial effects on upper airway mechanics. The ability to rapidly modulate airway mechanics with these vasoactive drugs further suggests that mucosal blood volume, rather than tissue edema, was the mechanism by which airway collapsibility was being changed. 9
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Upper Airway Imaging A representative Tl-weighted, midline sagittal view of the cat upper airway under control conditions is shown in figure 4. Contiguous transverse sections were taken in a region between the junction of the hard and soft palate and an area below the epiglottis. In this cat, the distance between the markers was 6.5 cm. Representative transverse views are
shown in figure 5 of the upper airway 3.2 em caudal to the junction of the hard and soft palate in the same cat before (A) and during (B) vasodilation. Note the region of the pharynx, which is indicated by the arrows. These images show that during vasodilation there was a large decrease in pharyngeal cross-sectional area attributable to increased thickness of the posterior wall of the pharnyx. A plot of pharyngeal cross-sectional area as a function of the distance caudal to the junction of the hard and soft palate during control and vasodilated conditions for all seven animals is shown in figure 6. Note that significant effects were observed at distances between 2.8 and 3.6 em caudaL The greatest effect was at 3.5 ± 0.4 em caudal, and at this site crosssectional area was decreased from 0.44 ± 0.10 to 0.30 ± 0.09 em" (p < 0.05). Additionally, cross-sectional area tended to decrease during vasodilation in the region of the hypopharynx. Under control conditions, the volume of the pharynx was 15.3 ± 2.4 ern" and was decreased to 13.9 ± 2.7 em" during vasodilation (p < 0.05). T2-weighted scans were used to determine the relative changes in pharyngeal
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The effect of vascular tone on upper airway elastic properties was examined by measuring static compliance in three animals. An example of the volumepressure relationships is shown in figure 3. Over a wide range of pressures from just above closing pressure to + 5 em H 20 , there was no difference between the upper airway volume-pressure relationships during control, vasodilation, and vasoconstriction. However, at the larger volumes vasodilation tended to shift the curve to the left (decreased compliance), whereas vasoconstriction tended to shift the curve to the right (increased compliance). Therefore, vascular tone did not affect the elastic properties of the airway in a manner that can explain the observed changes in closing and opening pressures.
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1575
VASCULAR TONE AND UPPER AIRWAY COLLAPSIBILITY
Fig. 9. Representative T1-weighted midline sagittal view of the upper airway during application of a negative pressure at the tracheal catheter. This was done to show the anatomic site of airway collapse. Note that the initial site of collapse was near the free margin of the soft palate.
on upper airway collapsibility provides evidence that the blood volume of mucosal tissue plays a role in the pharyngeal airway similar to that previously described for the nasal airway. Moreover, the points of maximal vasoconstriction and maximal vasodilation represent the ends of a spectrum over which vascular tone can modulate upper airway mechanics. As can be observed in figure 2, this is a range of approximately 5 em H 2 0 for closing pressure and nearly 7 ern H 2 0 for opening pressure. Consistent with the findings of other investigators (5), upper airway opening pressure was consistently more positive than closing pressure under all condi tions. This was presumably the result of surface-active forces that tend to perpetuate airway collapse once it has occurred. Although not statistically significant, it is interesting that this difference between opening and closing pressures appeared to be accentuated during vasodilation and diminished during vasoconstriction, implying that the pharynx was not only more collapsible but that its mucosa was "stickier" in the vasodilated state. The animals in this experiment had been premedicated with atropine sulfate in
order to minimize secretions, and it is possible that this intervention masked a significant effect of vascular tone on surface-active forces. During vasodilation, the mechanism by which the upper airway becomes more collapsible does not appear to be a change in the elastic properties of the airway. Measurement'of airway static compliance revealed that within the range of interest the VOlume-pressurerelationship was independent of vascular tone. This does not imply that mechanical properties of tissues did not change. At airway pressures greater than + 5 em H 20 , the airway appeared less compliant during vasodilation and more compliant during vasoconstriction. However, the differences between the volume-pressure curves at more positive pressures are probably the result of volume limitation of the airway. It is also possible that tissue compliance was affected by vascular tone, but that these effects were too small to significantly affect the overall volume-pressure relationship of the airway. The lack of a change in airway compliance suggests that the mechanism of increased collapsibility of the airway during vasodilation is a decrease in airway
cross-sectional area. The MRI confirmed this by showing that at the same dose of sodium nitroprusside sufficient to cause as much as a 30% decrease in closing pressure, pharyngeal cross-sectional area was reduced as much as 390/0. This was not a diffuse response, however, since the only significant effects on area were observed in the pharynx between 2.8 and 3.6 ern caudal to the junction of the hard and soft palate. Hypopharyngeal (4.4 ern caudal to the junction of the hard and soft palate) area also tended to decrease during vasodilation. Thus, we have observed the greatest effects of vascular tone on cross-sectional area of the pharyngeal region found to be most collapsible. Interestingly, the two pharyngeal segments in which a response to vasodilation was observed are also the most common sites of collapse in patients with obstructive sleep apnea (12). The decrease in pharyngeal cross-sectional area observed during vasodilation appears to be the result of increased volume of pharyngeal mucosal tissue. During vasodilation the posterior wall of the pharynx increased in thickness, causing a substantial decrease in pharyngeal cross-sectional area. Because the posterior wall of this region of the pharynx consists almost exclusively of mucosa with little supporting soft tissue, we believe that vasodilation led to an increase in the volume of this distensible mucosa, causing a reduction in pharyngeal airway caliber. Several lines of evidence suggest that increased blood volume accounts for the increased thickness of the pharyngeal mucosa. The T2-weighted scans show significant increases in tissue water content in the pharyngeal airway during vasodilation. Although the increase in water content could be in part the result of edema, we have shown that infusion of the vasoconstrictive agent phenylephrine after the infusion of the vasodilating agent sodium nitroprusside resulted in an immediate change in airway closing pressure to a more negative value. The rapidity of these changes suggest fluctuations in intravascular blood volume rather than in extravascular water. Furthermore, images obtained after infusion of an intravascular contrast agent, Gd-DTPA, clearly indicated an increase in mucosal blood volume during vasodilation. Changes in mucosal blood volume could be mediated by various mechanisms, including autonomic vasomotor acti vity, systemic venous pressure, or local factors related to trauma or inflammation. We have shown that vascular
1576
tone and mucosal blood volume are important nonmuscular determinants of upper airway collapsibility. Wespeculate that neurogenic vasomotor control of pharyngeal mucosal blood volume acts in concert with the neurogenic mechanisms controlling upper airway skeletal muscle activity to prevent pharyngeal collapse. Similar to neurogenic motor output to the upper airway skeletal muscles, sympathetic output is known to have a respiratory-synchronous component (13), and this output has been shown to parallel the activity of the phrenic nerve during both brain hypoxia and hypercapnia (14). This respiratory-synchronous sympathetic output is especially prevalent in the activity of the cervical sympathetic nerve, which supplies vasomotor innervation to the vasculature of the head and neck. We speculate that this increase in sympathetic activity during inspiration provides a breath-to-breath increase in vascular tone, which functions to decrease the collapsibility of the airway. It is not yet known if the time constants of contraction and relaxation of vascular smooth muscle are short enough to allow significant within-breath control of the pharyngeal vasculature. However, a recent study has revealed this type of control in the nasal airway. Haxhiu and coworkers (8) have shown, also in anesthetized, paralyzed cats, that nasal airway resistance decreases in phase with inspiration; this effect could be blocked by infusion of the alpha-antagonist, phentolamine. Therefore,since breath-to-breath variation in the vascular tone of the upper airway exists, control of pharyngeal collapsibility on the same time scale is also possible. This study was performed in anesthetized, paralyzed cats to control physiologic variables other than vascular tone, most notably blood pressure, airway pressure, and skeletal muscle activity. Clearly, caution is appropriate when speculating about the significance of our findings to human pathophysiology. However, we have recently completed another study in which we found that topical pharyngeal application of phenylephrine increased nasopharyngeal cross-sectional area 18070 and oropharyngeal cross-sectional area 14070 in normal human subjects (14). Thus, as we have shown in the cat, pharyngeal vascular tone is an important determinant of pharyngeal size in humans. Even in the presence of skeletal muscle activity, changes in vascular tone still have a significant influence on upper airway caliber.
WASICKO, HUTT, PARISI, NEUBAUER, MEZRICH, AND EDELMAN
The results of the present study lead us to speculate that alterations in the mucosal volume of the pharyngeal airway may playa role in the predisposition to collapse during sleep. Idiopathic obstructive sleep apnea (GSA) is characterized by repeated episodes of nocturnal upper airway obstruction. Collapse ofthe airway in patients with GSA has been shown to occur primarily at the level of the pharynx (1, 2, 12). Previous studies have shown that patients with GSA have abnormally narrow pharyngeal airways (15, 16), and as a result high pharyngeal resistance (17, 18). Additionally, upper airway closing pressures have been shown to be less negative in patients with GSA than in normal subjects (19). Despite this, no specific anatomic abnormality can be identified in most patients although it has been commonly observed in patients with GSA that the pharyngeal mucosa appears erythematous or edematous. This mucosal abnormality may be a consequence of repetitive barotrauma related to intermittent closure and reopening of the upper airway during sleep, and likely reflects increased mucosal blood volume or edema. In light of the large changes in pharyngeal collapsibility induced by changing mucosal blood volume in this study, we speculate that mucosal congestion in GSA may be an important mechanism perpetuating and exacerbating the GSA syndrome. Although we have focused on the influence of vascular tone on mucosal volume in the current study, we speculate that other factors such as increased systemic venous pressure associated with right heart failure or increased capillary permeability caused by local release of inflammatory mediators may ultimately be more relevant to the pathogenesis of OSA and related disorders. Patients with OSA are frequently hypertensive (20), a complication thought to be consequent to increased sympathetic nervous system stimulation by nocturnal hypoxemia. Because increased sympathetic output to the pharyngeal mucosal vasculature may playa role in resisting upper airway collapse, isolated therapy of hypertension with sympathetic blocking agents in this situation could theoretically worsen the disordered breathing. One attractive application of the results of this study is to the treatment of OSA. Vasoactive nasal sprays have been shown to decrease apneas during sleep, presumably by decreasing nasal airway resistance and thus decreasing the negative pressure in the pharnygeal airway (21). It is possible that application of a
vasoconstrictive agent favors patency of the pharynx directly. In summary, we have demonstrated that vascular tone significantly affects the size and collapsibility of the pharyngeal airway. Modulation of neural vasomotor output is thus another mechanism, in addition to skeletal muscle activity, by which pharyngeal mechanics can be actively and directly controlled. Acknowledgment The writers thank Theresa Hoang and Stacey LaBruno for technical assistance and Marcella Spioch for preparation of the manuscript. References 1. RemmersJE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44:931-8. 2. Guilleminault C, Hill M, Simmonds F, Dement We. Obstructive sleep apnea: electromyographic and fiberoptic studies. Exp Neuro11978; 62:48-67. 3. Brouillette R, Thach B.A neuromuscular mechanism maintaining extrathoracic airway patency. J Appl Physiol 1979; 46:772-9. 4. Van de Graaff WB. Thoracic influence on upper airway patency.J Appl Physiol1988; 65:2124-31. 5. Olson LG, Strohl KP. Non-muscular factors in upper airway patency in rabbit. Respir Physiol1988; 71:147-55. 6. Cole P. Nasal airflow resistance. In: Matthew OP, Sant'Ambrogio G, eds. Respiratory function of the upper airway. Vol.35: Lung biology in health and disease. New York: Marcel Dekker, 1988; 391-414. 7. Lung M, Wang J. Effects of hypercapnia and hypoxia on nasal vasculature and airflow resistance in the anesthetized dog. J Physiol (Lond) 1986; 373:261-75. 8. Haxhiu M, Deal E, Norcia M, van Lunteren E, Cherniak N. Effect of N-methyl-D-aspartate applied to the ventral surface of the medulla on the trachea. J Appl Physiol 1987; 63:1268-74. 9. Strohl K, Fouke J. Dilating forces on the upper airway of anesthetized dogs. J Appl Physiol1985; 58:452-8. 10. Hollander M, Wolff DA. Non-parametric statistical methods. New York: John Wiley, 1973; 155-8. II. Li JK-J, Wasicko MJ, Melton JE, Neubauer lA, Petrozzino JJ, Edelman NH. Tonic and respiratory-synchronous sympathetic modulation of systemic vascular tone during hypoxia or hypercapnia (abstract). FASEB J 1988; 2:A513. 12. Hudgel DW. Variable site of airway narrowing among obstructive sleep apnea patients. J Appl Physiol 1986; 61:1403-9. 13. Bainton C, Richter D, Seller H, Ballantyne D, Klein D. Respiratory modulation of sympathetic activity. J Auton Nerv Syst 1985; 12:77-90. 14. Parisi RA, Wasicko MJ, Hutt DA, Mandel M, Edelman NH. Mucosal vasoconstriction increases pharyngeal size in normal subjects (abstract). Am Rev Respir Dis 1989; 139:A374. IS. Haponik EF, Smith PL, Bohlman ME, Allen RP, Goldman SM, Bleeker ER. Computerized tomography in obstructive sleep apnea: correlation of airway size with physiology during sleep and wakefulness. Am Rev Respir Dis 1983; 127:221-6. 16. Suratt PM, Dee P, Atkinsen RL, Armstrong P, Wilhoit Se. Fluoroscopic and computerized tomographic features of the pharyngeal airway in
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VASCULAR TONE AND UPPER AIRWAY COLLAPSIBILITY
obstructive sleep apnea. Am Rev Respir Dis 1983; 127:487-92. 17. Anch A, Remmers J, Bunce H. Supraglottic airway resistance in normal subjects and patients with occlusive sleep apnea. J Appl Physiol 1982; 53:1158-63. 18. Stauffer JL, Zwillich CW, Codieux RJ, et 01.
Pharyngeal size and resistance in obstructive sleep apnea. Am Rev Respir Dis 1987; 136:623-7. 19. Issa FG, Sullivan CEo Upper airway closing pressures in obstructive sleep apnea. J Appl Physiol 1984; 57:520-7. 20. Guilleminault C. Natural history, cardiac impact, and long-term followup of sleep apnea syn-
drome. In: Guilleminault C, Lugaresi E, eds. Sleepwake disorders. New York: Raven Press, 1983; 107-25. 21. Wynne JW. Obstruction of the nose and breathing during sleep. Chest 1982; 82:657-8.
MICHAEL J. WASICKO, DOUGLAS A. HUTT, RICHARD A. PARISI, JUDITH A. NEUBAUER, REUBEN MEZRICH, and NORMAN H. EDELMAN With the technical assistance of Judith Gronlund-Jacob and Donna Chigi
Introduction
During normal eupneic breathing, the negative pressure generated by the thoracic pump muscles favors collapse of the upper airway. The principal defense of upper airway patency has been thought to be activation of upper airway skeletal muscles. However, nonmuscular mechanical properties of upper airway components such as connective tissue, blood vessels, and mucosa must also be important. Knowledge of mechanisms that influence upper airway collapsibility 1S important in understanding the pathogenesis of obstructive sleep apnea since this condition is characterized by increased pharyngeal collapsibility during sleep(1, 2). The structural and functional basis of this disorder is still unclear. A number of investigators have shown the importance of skeletal muscles in controlling pharyngeal patency. Activation of pharyngeal dilator muscles, such as the genioglossus, decreases upper airway resistance and collapsibility (1, 3). Additionally, caudal traction of the trachea by the cervical strap muscles can also reduce upper airway resistance (4). The role of nonmuscular factors in the active control of airway patency is less well understood. However, it has been suggested that these factors may also modulate airway collapse. Olson and Strohl (5) have shown in anesthetized rabbits that paralysis of skeletal muscles does not change upper airway closing or opening pressures during ventilation with 100070 O 2 and does not abolish the augmentation by hypercapnia of the upper airway's resistance to collapse. These investigators concluded that upper airway dilator muscle contraction is not essential to the ability of the pharynx to resist collapse and that nonmuscular factors might play an important role. One nonmuscular factor subject to active central neural control is vasomotor tone of the upper airway soft tissues. In
SUMMARY Upper airway collapsibility may be influenced by both muscular and nonmuscular factors. Because mucosal blood volume (and therefore vascular tone) is an important determinant of nasal airway patency, vascular tone may be an important nonmuscular determinant of pharyngeal collapsibility. This hypothesis was tested in two experimental models. First, upper airway closing (CP) and opening (OP) pressures and static compliance were measured in nine anesthetized, sinoaortic-denervated, paralyzed cats with isolated upper airways. Vascular tone was decreased with either papaverine or sodium nitroprusside (NTP), and increased with phenylephrine (PE), whereas blood pressure and end-tidal CO2 were maintained constant. Vasodilation increased CP (control = -10.4 ± 1.3, NTP = -7.3 ± 1.2 cm H20; P < 0.05) and OP (control = -7.9 ± 1.5, NTP = -3.3 ± 1.8 cm H20; p < 0.05). In contrast, vasoconstriction tended to decrease CP (control = -10.7 ± 1.5, PE = -11.7 ± 1.4 cm H20; p < 0.09) and OP (control = -8.1 ± 1.2, PE = -9.9 ± 1.9 cm H20; P < 0.1). Thus, vasodilation increased and vasoconstriction tended to decrease upper airway collapsibility. Upper airway static compliance was unchanged during either drug infusion. In order to assess changes in pharyngeal cross-sectional area (CSA)that occurred during vasodilation, magnetic resonance imaging was utilized in seven cats. During vasodilation with NTP, pharyngeal CSA was reduced from 0.44 ± 0.10 to 0.30 ± 0.09 em" (p < 0.05), and pharyngeal volume was reduced from 15.3 ± 2.4 to 13.9 ± 2.7 ern" (p < 0.05). The decrease in pharyngeal caliber was largely attributable to increased thickness of the posterolateral pharyngeal mucosa. Vascular tone appears to be an important nonmuscular determinant of upper airway collapsibility. AM REV RESPIR DIS 1990; 141:1569-1577
the nose, vascular tone and mucosal blood volume are dynamically controlled and are important determinants of nasal airway patency. Nasal resistance decreases when vascular tone is increased pharmacologically (6) or when sympathetic activity is increased with either hypercapnia (7) or application of the excitatory amino acid N-methyl-n-aspartate to the ventral surface of the medulla (8). Because mucosal blood volume is important in regulating nasal airway patency, we hypothesized that control of pharyngeal mucosal vascular tone is an important nonmuscular determinant of pharyngeal collapsibility. Specifically, we hypothesized that decreased vascular tone, and the subsequent increased mucosal blood volume, would result in a more collapsible upper airway. We tested this hypothesis in anesthetized, paralyzed supine cats using two experimental paradigms. First, the range of the effect of vascular tone on pharyngeal collapsibility was determined by measuring upper airway closing and opening pressures and static compliance while maxi-
mal vasodilation and vasoconstncnon wereinduced pharmacologically. Second, magnetic resonance imaging (MRI) was used to observe the changes in upper airway anatomy that occurred during changes in vascular tone. Methods General Preparation Collapsing pressures. Nine adult cats weigh(Received in original form August 7, 1989and in revised form December 4, 1989) 1 From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, and the Department of Radiology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey. 2 Supported by Research Grant No. HL-01549 and HL-16022 and Training Grant No. HL-07467 from the National Heart, Lung, and Blood Institute, and by Fellowship Award No. 88-049 from the American Heart Association/New Jersey Affiliate. 3 Correspondence and requests for reprints should be addressed to Richard A. Parisi, M.D., Division of Pulmonary and Critical Care Medicine, UMDNJRobert Wood Johnson Medical School, One Robert Wood Johnson Place-CN 19, New Brunswick, NJ 08903-0019.
1569
1570
WASICKO, HUTT, PARISI, NEUBAUER, MEZRICH, AND EDELMAN
ing between 2.5 and 4 kg were preanesthetized paralyzed, and mechanically ventilated as desure generation at the tracheal catheter within a wide range. intramuscularly with a mixture of ketamine scribed above. A femoral artery and both femHCI 00 mg/kg) and acepromazine (1.1 mg/ oral veins were cannulated for measurement Upper airway static compliance was meakg). Anesthesia was subsequently maintained of arterial blood gas tensions and pH and adsured by changing the volume of the upper intravenously with alpha-chloralose (20 to 40 ministration of the vasodilating agent sodiairway by known amounts above or below its um nitroprusside as well as anesthetics. mg/kg, supplemented regularly). Rectal temresting volume and recording the concomiperature was monitored and maintained at The carotid sinus nerves and vagi were left tant change in either nasal or tracheal pres38° C with a heating pad. Brachial arterial intact, and the cervical sympathetic nerves sure. The change in airway volume was plotted against the change in airway pressure. were sectioned bilaterally in the neck. Presand venous catheters were inserted for meaVascular tone was altered pharmacologisurement of blood pressure (Statham 23Db ervation of baroreflexes allowed the animal cally with vasoconstriction produced by inpressure transducer; Statham Instruments, to maintain a constant arterial blood presfusion of phenylephrine and vasodilation proOxnard, CA) and administration of anesthetics. sure during the infusion of sodium nitroprusA midline abdominal incision was perside, whereas sectioning of the cervical symduced by infusion of either papaverine (n = formed, and the abdominal aorta and inferipathetic nerves removed neurogenic vasomo2) or sodium nitroprusside (n = 7). The drugs tor influences on the upper airway. The tongue or vena cava were isolated and ligated just were slowly and continuously infused intrawas pulled anteriorly and secured to the low- venously with a monostaltic pump (Buchler proximal to the bifurcation of the femoral arteries. A low resistance, high capacitance res- er lip to prevent prolapse into the airway. The Instruments, Fort Lee, NJ) such that the doses ervoir containing isosmotic mannitol was conanimals were then placed in a semicylindrical were approximately 10 ug/kg/rnin for phennected to the descending aorta, and its height holder in the supine position with the neck ylephrine, and 20 ug/kg/min for sodium was adjusted to maintain systemic arterial slightly extended. In two cats the upper airnitroprusside. Papaverine was given at a conblood pressure constant at a mean level of way was isolated and sealed, as described stant dose of2 rug/kg at a rate of 0.1 mllmin. approximately 90 mm Hg. Phenylephrine and sodium nitroprusside were above, before MRI. This was done to identiThe trachea was isolated low in the neck fy the site of collapse during the generation infused to a steady state with respect to inand sectioned approximately I em below the of a negative pressure. travascular volume as estimated by the height larynx. Care was taken to ensure that the upof the aortic reservoir column (mean ± SE Protocol per airway muscles remained intact. A mark total doses: phenylephrine = 288 ± 29Ilg/kg; was made at the site of sectioning so that the sodium nitroprusside = 169 ± 56 ug/kg), Collapsing pressures. In order to prevent hyptrachea and the upper airway muscles could oxia, the animals were ventilated with 40% Upper airway closing and opening pressures be extended to their natural positions during O 2 , The cats were in the supine position, and and static compliance were measured before, the experimental procedure. The caudal tracare was taken to maintain a constant amount during, and 30 to 60 min after discontinuing chea was cannulated for mechanical ventilaof neck flexion for the duration of the ex- the infusion of either the vasodilating or tion. The cats were paralyzed (gallamine triperiment; typically, the head was at a 20 to vasoconstricting agent; both vasodilation and ethiodide) and mechanically ventilated while vasoconstriction were tested in each animal 40-degree angle with the spine. end-tidal CO 2 was maintained constant at 4.5 in a random order. The closing and opening The method of determining upper airway to 5.0070 by adjustment of the ventilator freclosing and opening pressures in this isolated pressures obtained under each experimental quency. The vagus nerves were sectioned system is illustrated in figure 1. This shows condition were the average of five determibilaterally in the neck. The carotid sinus nerves simultaneous recordings of nasal and trachenations. Upper airway static compliance was were also sectioned bilaterally through small al pressures while negative pressure was genermeasured only after an effect of the vasoacincisions on the ventrolateral surface of the ated at the tracheal catheter. When nasal prestive drug was observed. neck in the region of the carotid sinus. This Upper airway imaging. A-0.6 Tesla magsure was equal to tracheal pressure, upper airapproach was chosen to minimize disruption way patency was inferred. The pressure at net (Teslacon, Technicare, Solon, OH) was of the upper airway. used for these experiments. A human neck which there was discordance between the reThe upper airway was then isolated by the cordings was defined as the upper airway closcoil was positioned around the animal to almethods previously described by Brouillette ing pressure. As tracheal pressure was returned low imaging of the head and neck region. The and Thach (3) and Strohl and Fouke (9). The toward atmospheric pressure, nasal pressure animal was centered visually with the aid of rostral end of the sectioned trachea was caninitially remained constant and then abruptlaser cross-hairs, and moved into the MRI apnulated with a large-bore catheter positioned ly increased along with tracheal pressure, inparatus. The animals remained in this posicaudal to the vocal cords. The catheter was dicating the airway had become patent. The tion for the duration of the experiment. connected to a lO-ml syringe through which tracheal pressure at which airway patency was In this study, magnetic resonance imaging pressure could be generated. A second cathereestablished was defined as the upper airwas performed using the spin echo technique, ter was inserted into the nares, and the tip way opening pressure. Both closing and opena powerful method that utilizes differences was positioned approximately 0.5 ern anteriing pressures were found to be reproducible in the dynamic behavior of hydrogen nuclei or to the junction of the hard and soft palate. under each experimental condition, and were in a magnetic field to perturbation by a series The tongue was pulled an teriorly, and the found to be independent of the rate of presof radio frequency pulses. The information buccal cavity and nose were sealed with glazing compound and cyano-acrylate to create a closed sytem. The upper airway was con5 sidered sealed if a pressure of ± 10 cm H 2 0 could be held for 20 to 30 s. Care was taken 0 during the preparation not to disrupt arterial aN Fig. 1. Technique for determining airsupply to the pharynx or to physically ma- :r: -5 E way closing and opening pressures in nipulate the pharyngeal mucosa. Both the na- ~ PNASAL 7 + - OPENING PRE5SUllE the sealed, isolated upper airway. Simulw -10 sal and tracheal catheters were connected to a::: Q.OSINCPRESSURE --+ •••,.--•• ------ •• - - - .1 taneous nasal and tracheal pressures ::> differential pressure transducers (Validyne l/) l/) are shown while a negative pressure w -15 Corp., Northridge, CA) referenced to atD::: was generated and released at the traa.. mospheric pressure. cheal catheter. See text for details. -20 Upper airway imaging. The size constraints of the MRI apparatus required changes in the -25 0 10 15 above experimental model. Seven cats weigh5 20 25 ing between 2.5 and 3 kg were anesthetized, TIME (SEC)
1571
VASCULAR TONE AND UPPER AIRWAY COLLAPSIBILITY
is then used to generate images of graded intensity noninvasively and without ionizing radiation. Relative dependence of image intensity on either of two time constants, Tl and T2, can be controlled by varying two pulse sequence parameters, repetition time (T R) and echo time (T d. In this study, both Tlweighted (T R = 500 ms, T E = 33 ms) and T2-weighted (TR = 2,000 ms, T E = 110ms) scans were performed. Tl-weighted images, which provide better overall contrast, were used to define the anatomy of the upper airway.On T2-weighted images, intensity is most closely related to water content. These images were therefore used to assess relative changes in interstitial tissue water or blood. Both sagittal and transverse views of the upper airway were used, and the sequence of scanning was as follows. First, Tl-weighted sagittal views of the upper airway were used to define the region in which transverse sections would be taken. This region started at the junction of the hard and soft palate and continued caudally to a region below the epiglottis. Serial, contiguous Tl-weighted transverse sections (4 mm thick) were then made in this region. Transverse views allowed for the calculation of pharyngeal cross-sectional area and volume. Noncontiguous T2-weighted transverse scans (6 mm thick with 1 mnvspacing) were then obtained. Upper airway anatomy and mucosal water content were examined under control conditions and after vasodilation with continuous intravenous infusion of sodium nitroprusside. Because there was no available index to assure that a steady-state effect had been achieved with sodium nitroprusside, the animals were given the same total dose found to maximally decrease airway closing pressure in the first series of studies (200 ug/kg). In two cats, the site of airway collapse during application of negative pressure was determined by utilizing sagittal TI images. In these cats, the upper airway was isolated and sealed as described in the first protocol. The airway was collapsed by generating a negative pressure at the tracheal catheter. Because pressure was not recorded, the airway was assumed to be collapsed if air could no longer be removed through the tracheal catheter.
Data Analysis In the experiments using the sealed upper airway model, it was found that under any experimental condition significant interanimal differences in airway closing and opening pressures were present, and the data were determined to be nonparametric. To account for this, Friedman's rank sum test (10) was used to compare control closing and opening pressures to both those obtained during the drug infusion and postdrug infusion. A level of 0.05 was considered to be significant. Changes in upper airway static compliance during the infusion of the vasoactive drug were assessed by inspection of the volume-pressure relationships. . In the MRI studies, pharyngeal cross-sectional area was plotted as a function of the
TABLE 1 ARTERIAL BLOOD PRESSURE AND END-TIDAL CO2 DURING VASODILATION AND VASOCONSTRICTION
Condition Control (vasodilation runs) Vasodilation Control (vasoconstriction runs) Vasoconstriction Definition of abbreviations: PAP
Drug
Dose
PAP NTP
2 mg/kg 169 ± 56 Ilg/kg
PE
288 ± 29 Ilg/kg
= papaverine;
NTP
=
nitroprusside; PE
distance caudal from the junction of the hard and soft palate for both control and vasodilated conditions. Because the transverse sections used in this study were of a constant thickness, area was measured every 4 mm. At each point the control area was compared with the area obtained during vasodilation via paired t-test. Additionally, the volume of the pharyngeal airway was calculated by integrating the area-distance function. The volumes calculated during control and vasodilated conditions were compared using the paired t-test. A levelof 0.05 was considered significant. T2weighted scans were inspected for changes in water content in the pharyngeal mucosa. Results
Collapsing Pressures The values of end-tidal CO 2 and blood pressure are shown in table 1 for control conditions and during vasodilation and vasoconstriction. Note that two sets of control measurements are shown - one obtained before vasodilation and the other before vasoconstriction. Neither endtidal CO 2 nor blood pressure changed significantly during vasodilation or vasoconstriction. The mean airway closing and opening pressures obtained before, during, and after vasodilation and vasoconstriction are shown in figure 2. Control closing pressures were similar prior to vasodilation (-lOA ± 1.3 em H 20; range, -4.0 to -15.1 em H 20) and vasoconstriction (-10.7 ± 1.5 ern H 20; range, - 5.3 to -18.9 em H 20). Control opening pres-
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5.0 ± 0.1 5.3 ± 0.2
93.2 ± 4.3 91.7 ± 3.7
5.0 ± 0.1 5.0 ± 0.2
= phenylephrine.
Fig. 2. The effect of vasodilation (left panel) and vasoconstriction (right panel) on closing and opening pressures (n = 9). Pressures are shown for control, drug infusion, and 30 min after drug infusion. Note that vasodilation resulted in an airway that was more collapsible, whereas vasoconstriction resulted in an airway that was less collapsible. Asterisks indicate p < 0.05.
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93.2 ± 4.3 89.1 ± 5.7
sures were -7.9 ± 1.5 em H 20 (range, - 2.3 to -12.9 em H 20) before vasodilation and - 8.1 ± 1.2 em H 20 (range, - 2.1 to -12.9 cm H 20) before vasoconstriction. Control measurements of each parameter repeated after withdrawal of either treatment were not different from the initial baseline values. During vasodilation, both closing and opening pressures wereless negative. Closing pressure increased to - 7.3 ± 1.2 em H 20 and opening pressure to - 3.3 ± 1.8 cm H 20 during infusion of sodium nitroprusside (n = 7) or papaverine (n = 2). All nine animals followed this trend during vasodilation (p < 0.01). In two animals, airway opening pressure increased dramatically to supra-atmospheric levels: -1.9 to + 2.8 ern H 20 in one, and - 8.8 to + 5.7 em H 20 in the other. In contrast, during vasoconstriction, closing pressure tended to become more negative. Closing pressure decreased to -11.7 ± 1.4 em H 20 during infusion of phenylephrine. This difference was not statistically different from control values (p < 0.09) because five of nine animals had no response to vasoconstriction despite large doses of phenylephrine. Opening pressure during vasoconstriction was - 9.9 ± 1.9 cm H 20, and although this tended to be more negative than the control values, the difference was not statistically significant. The minimal effect of phenylephrine on airway closing and opening pressures
1
.,
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VASOCONSTRICTION
VASODILATION
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1572
WASICKO. HUTT, PARISI, NEUBAUER, MEZRICH, AND EDELMAN
suggested that the mucosal vessels were already in a relatively vasoconstricted state. This was likely since we have found in other experiments using similarly prepared (anesthetized, barodenervated, vagotomized) cats that systemic vascular resistance is quite high (11). Thus, infusion of the vasoconstrictive agent phenylephrine could have had little additional effect on the vasculature. To test this, phenylephrine was infused immediately after closing and opening pressures had been increased by vasodilation with sodium nitroprusside in one cat. Because the effect of this vasodilating agent on airway closing and opening pressure was found to last 30 to 60 min after the infusion was discontinued, an immediate and opposite effect (within a few minutes) of phenylephrine would suggest that vasoconstriction with this agent does not have a direct effect on pharyngeal collapsibility. In this animal, a dose of 50 ug/kg sodium nitroprusside increased closing pressure from -10.4 to - 3.2 cm H 2 0 . Infusion of phenylephrine immediately after the removal of sodium nitroprusside decreased closing pressure to -12.0 em H 2 0 within 3.5 min. Therefore, both vasodilation and vasoconstriction produced substantial effects on upper airway mechanics. The ability to rapidly modulate airway mechanics with these vasoactive drugs further suggests that mucosal blood volume, rather than tissue edema, was the mechanism by which airway collapsibility was being changed. 9
CONTROL 6NTP o PHENYL
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Upper Airway Imaging A representative Tl-weighted, midline sagittal view of the cat upper airway under control conditions is shown in figure 4. Contiguous transverse sections were taken in a region between the junction of the hard and soft palate and an area below the epiglottis. In this cat, the distance between the markers was 6.5 cm. Representative transverse views are
shown in figure 5 of the upper airway 3.2 em caudal to the junction of the hard and soft palate in the same cat before (A) and during (B) vasodilation. Note the region of the pharynx, which is indicated by the arrows. These images show that during vasodilation there was a large decrease in pharyngeal cross-sectional area attributable to increased thickness of the posterior wall of the pharnyx. A plot of pharyngeal cross-sectional area as a function of the distance caudal to the junction of the hard and soft palate during control and vasodilated conditions for all seven animals is shown in figure 6. Note that significant effects were observed at distances between 2.8 and 3.6 em caudaL The greatest effect was at 3.5 ± 0.4 em caudal, and at this site crosssectional area was decreased from 0.44 ± 0.10 to 0.30 ± 0.09 em" (p < 0.05). Additionally, cross-sectional area tended to decrease during vasodilation in the region of the hypopharynx. Under control conditions, the volume of the pharynx was 15.3 ± 2.4 ern" and was decreased to 13.9 ± 2.7 em" during vasodilation (p < 0.05). T2-weighted scans were used to determine the relative changes in pharyngeal
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The effect of vascular tone on upper airway elastic properties was examined by measuring static compliance in three animals. An example of the volumepressure relationships is shown in figure 3. Over a wide range of pressures from just above closing pressure to + 5 em H 20 , there was no difference between the upper airway volume-pressure relationships during control, vasodilation, and vasoconstriction. However, at the larger volumes vasodilation tended to shift the curve to the left (decreased compliance), whereas vasoconstriction tended to shift the curve to the right (increased compliance). Therefore, vascular tone did not affect the elastic properties of the airway in a manner that can explain the observed changes in closing and opening pressures.
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1575
VASCULAR TONE AND UPPER AIRWAY COLLAPSIBILITY
Fig. 9. Representative T1-weighted midline sagittal view of the upper airway during application of a negative pressure at the tracheal catheter. This was done to show the anatomic site of airway collapse. Note that the initial site of collapse was near the free margin of the soft palate.
on upper airway collapsibility provides evidence that the blood volume of mucosal tissue plays a role in the pharyngeal airway similar to that previously described for the nasal airway. Moreover, the points of maximal vasoconstriction and maximal vasodilation represent the ends of a spectrum over which vascular tone can modulate upper airway mechanics. As can be observed in figure 2, this is a range of approximately 5 em H 2 0 for closing pressure and nearly 7 ern H 2 0 for opening pressure. Consistent with the findings of other investigators (5), upper airway opening pressure was consistently more positive than closing pressure under all condi tions. This was presumably the result of surface-active forces that tend to perpetuate airway collapse once it has occurred. Although not statistically significant, it is interesting that this difference between opening and closing pressures appeared to be accentuated during vasodilation and diminished during vasoconstriction, implying that the pharynx was not only more collapsible but that its mucosa was "stickier" in the vasodilated state. The animals in this experiment had been premedicated with atropine sulfate in
order to minimize secretions, and it is possible that this intervention masked a significant effect of vascular tone on surface-active forces. During vasodilation, the mechanism by which the upper airway becomes more collapsible does not appear to be a change in the elastic properties of the airway. Measurement'of airway static compliance revealed that within the range of interest the VOlume-pressurerelationship was independent of vascular tone. This does not imply that mechanical properties of tissues did not change. At airway pressures greater than + 5 em H 20 , the airway appeared less compliant during vasodilation and more compliant during vasoconstriction. However, the differences between the volume-pressure curves at more positive pressures are probably the result of volume limitation of the airway. It is also possible that tissue compliance was affected by vascular tone, but that these effects were too small to significantly affect the overall volume-pressure relationship of the airway. The lack of a change in airway compliance suggests that the mechanism of increased collapsibility of the airway during vasodilation is a decrease in airway
cross-sectional area. The MRI confirmed this by showing that at the same dose of sodium nitroprusside sufficient to cause as much as a 30% decrease in closing pressure, pharyngeal cross-sectional area was reduced as much as 390/0. This was not a diffuse response, however, since the only significant effects on area were observed in the pharynx between 2.8 and 3.6 ern caudal to the junction of the hard and soft palate. Hypopharyngeal (4.4 ern caudal to the junction of the hard and soft palate) area also tended to decrease during vasodilation. Thus, we have observed the greatest effects of vascular tone on cross-sectional area of the pharyngeal region found to be most collapsible. Interestingly, the two pharyngeal segments in which a response to vasodilation was observed are also the most common sites of collapse in patients with obstructive sleep apnea (12). The decrease in pharyngeal cross-sectional area observed during vasodilation appears to be the result of increased volume of pharyngeal mucosal tissue. During vasodilation the posterior wall of the pharynx increased in thickness, causing a substantial decrease in pharyngeal cross-sectional area. Because the posterior wall of this region of the pharynx consists almost exclusively of mucosa with little supporting soft tissue, we believe that vasodilation led to an increase in the volume of this distensible mucosa, causing a reduction in pharyngeal airway caliber. Several lines of evidence suggest that increased blood volume accounts for the increased thickness of the pharyngeal mucosa. The T2-weighted scans show significant increases in tissue water content in the pharyngeal airway during vasodilation. Although the increase in water content could be in part the result of edema, we have shown that infusion of the vasoconstrictive agent phenylephrine after the infusion of the vasodilating agent sodium nitroprusside resulted in an immediate change in airway closing pressure to a more negative value. The rapidity of these changes suggest fluctuations in intravascular blood volume rather than in extravascular water. Furthermore, images obtained after infusion of an intravascular contrast agent, Gd-DTPA, clearly indicated an increase in mucosal blood volume during vasodilation. Changes in mucosal blood volume could be mediated by various mechanisms, including autonomic vasomotor acti vity, systemic venous pressure, or local factors related to trauma or inflammation. We have shown that vascular
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tone and mucosal blood volume are important nonmuscular determinants of upper airway collapsibility. Wespeculate that neurogenic vasomotor control of pharyngeal mucosal blood volume acts in concert with the neurogenic mechanisms controlling upper airway skeletal muscle activity to prevent pharyngeal collapse. Similar to neurogenic motor output to the upper airway skeletal muscles, sympathetic output is known to have a respiratory-synchronous component (13), and this output has been shown to parallel the activity of the phrenic nerve during both brain hypoxia and hypercapnia (14). This respiratory-synchronous sympathetic output is especially prevalent in the activity of the cervical sympathetic nerve, which supplies vasomotor innervation to the vasculature of the head and neck. We speculate that this increase in sympathetic activity during inspiration provides a breath-to-breath increase in vascular tone, which functions to decrease the collapsibility of the airway. It is not yet known if the time constants of contraction and relaxation of vascular smooth muscle are short enough to allow significant within-breath control of the pharyngeal vasculature. However, a recent study has revealed this type of control in the nasal airway. Haxhiu and coworkers (8) have shown, also in anesthetized, paralyzed cats, that nasal airway resistance decreases in phase with inspiration; this effect could be blocked by infusion of the alpha-antagonist, phentolamine. Therefore,since breath-to-breath variation in the vascular tone of the upper airway exists, control of pharyngeal collapsibility on the same time scale is also possible. This study was performed in anesthetized, paralyzed cats to control physiologic variables other than vascular tone, most notably blood pressure, airway pressure, and skeletal muscle activity. Clearly, caution is appropriate when speculating about the significance of our findings to human pathophysiology. However, we have recently completed another study in which we found that topical pharyngeal application of phenylephrine increased nasopharyngeal cross-sectional area 18070 and oropharyngeal cross-sectional area 14070 in normal human subjects (14). Thus, as we have shown in the cat, pharyngeal vascular tone is an important determinant of pharyngeal size in humans. Even in the presence of skeletal muscle activity, changes in vascular tone still have a significant influence on upper airway caliber.
WASICKO, HUTT, PARISI, NEUBAUER, MEZRICH, AND EDELMAN
The results of the present study lead us to speculate that alterations in the mucosal volume of the pharyngeal airway may playa role in the predisposition to collapse during sleep. Idiopathic obstructive sleep apnea (GSA) is characterized by repeated episodes of nocturnal upper airway obstruction. Collapse ofthe airway in patients with GSA has been shown to occur primarily at the level of the pharynx (1, 2, 12). Previous studies have shown that patients with GSA have abnormally narrow pharyngeal airways (15, 16), and as a result high pharyngeal resistance (17, 18). Additionally, upper airway closing pressures have been shown to be less negative in patients with GSA than in normal subjects (19). Despite this, no specific anatomic abnormality can be identified in most patients although it has been commonly observed in patients with GSA that the pharyngeal mucosa appears erythematous or edematous. This mucosal abnormality may be a consequence of repetitive barotrauma related to intermittent closure and reopening of the upper airway during sleep, and likely reflects increased mucosal blood volume or edema. In light of the large changes in pharyngeal collapsibility induced by changing mucosal blood volume in this study, we speculate that mucosal congestion in GSA may be an important mechanism perpetuating and exacerbating the GSA syndrome. Although we have focused on the influence of vascular tone on mucosal volume in the current study, we speculate that other factors such as increased systemic venous pressure associated with right heart failure or increased capillary permeability caused by local release of inflammatory mediators may ultimately be more relevant to the pathogenesis of OSA and related disorders. Patients with OSA are frequently hypertensive (20), a complication thought to be consequent to increased sympathetic nervous system stimulation by nocturnal hypoxemia. Because increased sympathetic output to the pharyngeal mucosal vasculature may playa role in resisting upper airway collapse, isolated therapy of hypertension with sympathetic blocking agents in this situation could theoretically worsen the disordered breathing. One attractive application of the results of this study is to the treatment of OSA. Vasoactive nasal sprays have been shown to decrease apneas during sleep, presumably by decreasing nasal airway resistance and thus decreasing the negative pressure in the pharnygeal airway (21). It is possible that application of a
vasoconstrictive agent favors patency of the pharynx directly. In summary, we have demonstrated that vascular tone significantly affects the size and collapsibility of the pharyngeal airway. Modulation of neural vasomotor output is thus another mechanism, in addition to skeletal muscle activity, by which pharyngeal mechanics can be actively and directly controlled. Acknowledgment The writers thank Theresa Hoang and Stacey LaBruno for technical assistance and Marcella Spioch for preparation of the manuscript. References 1. RemmersJE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44:931-8. 2. Guilleminault C, Hill M, Simmonds F, Dement We. Obstructive sleep apnea: electromyographic and fiberoptic studies. Exp Neuro11978; 62:48-67. 3. Brouillette R, Thach B.A neuromuscular mechanism maintaining extrathoracic airway patency. J Appl Physiol 1979; 46:772-9. 4. Van de Graaff WB. Thoracic influence on upper airway patency.J Appl Physiol1988; 65:2124-31. 5. Olson LG, Strohl KP. Non-muscular factors in upper airway patency in rabbit. Respir Physiol1988; 71:147-55. 6. Cole P. Nasal airflow resistance. In: Matthew OP, Sant'Ambrogio G, eds. Respiratory function of the upper airway. Vol.35: Lung biology in health and disease. New York: Marcel Dekker, 1988; 391-414. 7. Lung M, Wang J. Effects of hypercapnia and hypoxia on nasal vasculature and airflow resistance in the anesthetized dog. J Physiol (Lond) 1986; 373:261-75. 8. Haxhiu M, Deal E, Norcia M, van Lunteren E, Cherniak N. Effect of N-methyl-D-aspartate applied to the ventral surface of the medulla on the trachea. J Appl Physiol 1987; 63:1268-74. 9. Strohl K, Fouke J. Dilating forces on the upper airway of anesthetized dogs. J Appl Physiol1985; 58:452-8. 10. Hollander M, Wolff DA. Non-parametric statistical methods. New York: John Wiley, 1973; 155-8. II. Li JK-J, Wasicko MJ, Melton JE, Neubauer lA, Petrozzino JJ, Edelman NH. Tonic and respiratory-synchronous sympathetic modulation of systemic vascular tone during hypoxia or hypercapnia (abstract). FASEB J 1988; 2:A513. 12. Hudgel DW. Variable site of airway narrowing among obstructive sleep apnea patients. J Appl Physiol 1986; 61:1403-9. 13. Bainton C, Richter D, Seller H, Ballantyne D, Klein D. Respiratory modulation of sympathetic activity. J Auton Nerv Syst 1985; 12:77-90. 14. Parisi RA, Wasicko MJ, Hutt DA, Mandel M, Edelman NH. Mucosal vasoconstriction increases pharyngeal size in normal subjects (abstract). Am Rev Respir Dis 1989; 139:A374. IS. Haponik EF, Smith PL, Bohlman ME, Allen RP, Goldman SM, Bleeker ER. Computerized tomography in obstructive sleep apnea: correlation of airway size with physiology during sleep and wakefulness. Am Rev Respir Dis 1983; 127:221-6. 16. Suratt PM, Dee P, Atkinsen RL, Armstrong P, Wilhoit Se. Fluoroscopic and computerized tomographic features of the pharyngeal airway in
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obstructive sleep apnea. Am Rev Respir Dis 1983; 127:487-92. 17. Anch A, Remmers J, Bunce H. Supraglottic airway resistance in normal subjects and patients with occlusive sleep apnea. J Appl Physiol 1982; 53:1158-63. 18. Stauffer JL, Zwillich CW, Codieux RJ, et 01.
Pharyngeal size and resistance in obstructive sleep apnea. Am Rev Respir Dis 1987; 136:623-7. 19. Issa FG, Sullivan CEo Upper airway closing pressures in obstructive sleep apnea. J Appl Physiol 1984; 57:520-7. 20. Guilleminault C. Natural history, cardiac impact, and long-term followup of sleep apnea syn-
drome. In: Guilleminault C, Lugaresi E, eds. Sleepwake disorders. New York: Raven Press, 1983; 107-25. 21. Wynne JW. Obstruction of the nose and breathing during sleep. Chest 1982; 82:657-8.
