Published ahead of print on September 22, 2006, doi:10.1164/rccm.200607-927OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200607-927OC
Fluid Shift by Lower Body Positive Pressure Increases Pharyngeal Resistance in Healthy SubjectsSleep Research Laboratory, Toronto Rehabilitation Institute; Department of Medicine, Mount Sinai Hospital; Toronto General Hospital, University Health Network; Division of Otolaryngology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada Correspondence and requests for reprints should be addressed to T. Douglas Bradley, M.D., Toronto General Hospital/University Health Network, 9N-943, Toronto, ON, M5G 2C4 Canada. E-mail: douglas.bradley{at}utoronto.ca
Introduction: Fluid displacement into nuchal and peripharyngeal soft tissues while recumbent may contribute to narrowing and increased airflow resistance of the pharynx (Rph), and predispose to pharyngeal collapse in patients at risk for obstructive sleep apnea. Objectives: To determine whether displacement of fluid from the lower body to the neck will increase both neck circumference and Rph in healthy subjects. Methods: In 11 healthy, nonobese subjects, studied while awake and supine, leg fluid volume, neck circumference, and Rph were measured at baseline. Subjects were then randomized to a control period or to application of lower body positive pressure (LBPP) of 40 mm Hg via antishock trousers to displace fluid from the legs, after which they crossed over to the other arm. Baseline measurements were repeated at 1 and 5 min during the control and LBPP periods. Results: Compared with the control period, application of LBPP caused a significant reduction in leg fluid volume (p < 0.001) and a significant increase in neck circumference (p = 0.004). Rph remained stable during the control period, but increased significantly from baseline after 1 and 5 min of LBPP (from 0.43 ± 0.10 to 0.60 ± 0.11 cm H2O/L/s, p = 0.034, and to 0.87 ± 0.19 cm H2O/L/s, p < 0.001, compared with baseline, respectively). Conclusions: Fluid displacement from the legs by LBPP increases neck circumference and Rph in healthy subjects. These findings suggest the hypothesis that fluid displacement to the upper body during recumbency may predispose to pharyngeal obstruction during sleep, especially in fluid overload states, such as heart and renal failure.
Key Words: fluid displacement • lower body positive pressure • obstructive sleep apnea • pharyngeal resistance
A number of factors contribute to upper airway obstruction in patients with obstructive sleep apnea (OSA). Among these, obesity and neck circumference are important risk factors, but together only account for approximately one-third of the variability in the apnea–hypopnea index (1–3). Other factors must therefore contribute to upper airway obstruction. One such factor, not ordinarily considered, is fluid accumulation in the nuchal and peripharyngeal soft tissues. OSA is also very common in patients with fluid-retaining states, such as heart failure (HF) (4–8), renal failure (9, 10), and idiopathic peripheral edema (11). These observations suggest that fluid overload might contribute to the pathogenesis of OSA in some patients. It has been shown that systemic infusion of the vasodilators papaverine and nitroprusside caused a significant reduction of pharyngeal cross-sectional area in association with an increased thickness of the pharyngeal mucosa in cats (12). Conversely, topical application of a vasoconstrictor, phenylephrine, to the pharyngeal mucosa can decrease pharyngeal resistance (Rph) in healthy humans (13). Pharyngeal mucosal water content (i.e., edema) has also been reported to decrease after chronic application of continuous positive airway pressure to patients with OSA (14). These observations suggest that fluid accumulation in nuchal and peripharyngeal soft tissues may cause pharyngeal narrowing and increase the likelihood of pharyngeal occlusion in patients predisposed to OSA. Shepard and colleagues (15) first proposed that fluid displacement from the lower extremities to the upper body might play a role in narrowing the upper airway in patients with OSA. They tested the effects of shifting fluid into the neck by raising the legs, and of reducing venous return to the upper body by applying venous occlusive tourniquets around the thighs in patients with OSA. Using computed tomography, they found a tendency for pharyngeal cross-sectional area to decrease and increase in response to leg raising and tourniquet application, respectively, but these changes were not significant. Another potentially more effective, noninvasive means of displacing fluid from the lower extremities to the upper body is the application of lower body positive pressure (LBPP) by antishock trousers. This intervention increases central venous pressure in normal subjects (16, 17). In addition, a more sensitive means of detecting alterations in upper airway caliber than imaging techniques is alteration in Rph, because change in resistance is inversely proportional to the fourth power of the change in radius of the airway (18). Therefore, to mimic the effects of fluid redistribution from the lower to the upper body in patients with fluid overload while recumbent, we applied LBPP to healthy, nonobese, euvolemic subjects. We tested the hypothesis that an acute fluid shift from the lower to the upper body will increase Rph. Some of these data have been presented in abstract form (19).
Subjects Eligible subjects were healthy, nonobese (body mass index < 30 kg/m2) men and women 18 yr of age or older, with no history of smoking, or cardiovascular, respiratory, or neurologic disease, and no history of habitual snoring or daytime sleepiness. Exclusion criteria were pregnancy, a history of allergy to a local anesthetic, and use of prescribed medication. The protocol was approved by our institutional research ethics board, and all subjects gave their written, informed consent before participating.
LBPP
Leg Fluid Volume, Neck Circumference, and Pharyngeal Resistance After application of local anesthesia using a 10% lidocaine spray to the nose and the oropharynx, two open catheters (8 F, Med-Rx; Benlan, Inc., Oakville, ON, Canada) were introduced into one nostril. The first catheter was advanced to the back of the nose then withdrawn 0.5 cm to the choanae for measurement of nasopharyngeal pressure. The second catheter was advanced beyond the soft palate and base of the tongue to as far as the subjects could tolerate without gagging or discomfort, or to 18 cm from the nares, whichever was reached first, for measurement of hypopharyngeal (i.e., supraglottic) pressure (25). The catheters were secured with tape to the upper lip and remained in place throughout the experiments. Each catheter was connected to a separate differential pressure transducer (Validyne MP45; Validyne Engineering, Northridge, CA). These pressures were referenced to pressure measured inside a face mask. Flow was measured using a pneumotachograph (Hans Rudolph Model 4700; Hans Rudolph, Inc., Kansas City, MO) connected to a tightly fitting face mask (model 9000; Vital Signs, Inc., Totowa, NJ). The pressure gradient across the pneumotachograph was determined with a third differential pressure transducer. Pressure and flow signals were amplified and fed through an analog-to-digital converter, and then stored in a computer for later off-line analysis. Transpharyngeal pressure gradient (hypopharyngeal pressure – nasopharyngeal pressure) was also calculated by the computer. Rph was then calculated by dividing the transpharyngeal pressure gradient by airflow at an inspiratory flow of 0.3 L/s (25). Two to three milliliters of compressed air were injected through the proximal port of the catheters to clear secretions from the catheter tips as required.
End-Expiratory Lung Volume and Blood Pressure In four subjects who took part in the original experiments, we performed experiments on a separate day to determine the effects of LBPP on lung volumes using spirometry and multiple-breath helium dilution techniques as described in the American Thoracic Society/National Heart, Lung, and Blood Institute consensus document (27).
Protocol In the four subjects who returned on a separate occasion, after a 15-min baseline period, lung volumes were determined while supine by spirometry and multiple-breath helium dilution at the end of a 5-min control period and after 5 min of LBPP at 40 mm Hg in random order.
Data Analysis
Characteristics of the Subjects Eleven healthy subjects, seven males and four females, with a mean age of 36 ± 3 yr, a mean body mass index of 22.9 ± 1.0 kg/m2, and a mean neck circumference of 36.7 ± 1.4 cm, participated in this study. The characteristics of each subject are shown in Table 1.
Leg Fluid Volume, Neck Circumference, and Pharyngeal Resistance Figure 1 shows tracings of neck circumference, airflow, and transpharyngeal pressure gradient at the end of a baseline period, and after 1 and 5 min of LBPP from a representative subject. Compared with the baseline period, neck circumference and transpharyngeal pressure gradient increased after 1 and 5 min of LBPP.
Figure 2 shows grouped data for all 11 subjects. The p values shown in the plots were adjusted for multiple comparisons by Tukey's test. Compared with baseline, total leg fluid volume remained stable after 1 and 5 min during the control period (from 4.65 ± 0.47 to 4.66 ± 0.47 L, p = 0.961, and to 4.69 ± 0.47 L, p = 0.514, respectively; Figure 2A). However, after 1 and 5 min of LBPP, total leg fluid volume decreased compared with baseline (from 4.59 ± 0.47 to 4.42 ± 0.44 L, p < 0.001, and to 4.44 ± 0.44 L, p < 0.001). Reductions in leg fluid volume during LBPP were significantly greater compared with the control period at both 1 and 5 min (p < 0.001 for both comparisons).
Similarly, during the control period, neck circumference did not change significantly from baseline at either 1 or 5 min (by –0.05 ± 0.06%, p = 0.685, and by –0.03 ± 0.05%, p = 0.905; Figure 2B). However, neck circumference increased significantly from baseline after 1 and 5 min of LBPP (by 0.30 ± 0.07%, p < 0.001, and by 0.22 ± 0.09%, p < 0.005). These changes were significantly greater than at the 1- and 5-min control periods (p < 0.001 and p = 0.004, respectively). During the control period, Rph at 1 and 5 min did not differ from baseline (from 0.40 ± 0.06 to 0.39 ± 0.05 cm H2O/L/s, p = 0.697, and to 0.34 ± 0.05 cm H2O/L/s, p = 0.706, respectively; Figure 2C). In contrast, during LBPP, Rph increased significantly compared with baseline at both 1 and 5 min (from 0.43 ± 0.10 to 0.60 ± 0.11 cm H2O/L/s, p = 0.034, and to 0.87 ± 0.19 cm H2O/L/s, p < 0.001, respectively). The increase in Rph during LBPP after 1 min was 40% greater than at baseline. There was a further significant increase from 1 to 5 min that was 102% greater than at baseline. The change in Rph after 5 min of LBPP was also significantly greater than at the corresponding time during the control period (p = 0.002; Figure 2C).
EELV, Blood Pressure, and Heart Rate
In the four subjects who had lung volumes determined by spirometry and helium dilution, in comparison with control subjects, functional residual capacity increased while exposed to LBPP in all, but this increase was not statistically significant (from 2.70 ± 0.59 to 3.00 ± 0.71 L, p = 0.19). There was also a nonsignificant tendency for residual volume and total lung capacity to increase while receiving LBPP (from 1.72 ± 0.50 to 2.06 ± 0.58 L, p = 0.13, and from 5.87 ± 1.00 to 6.10 ± 1.08 L, p = 0.41, respectively). There were no side effects during the application of LBPP.
This study has given rise to several novel observations regarding the response of the nuchal structures and pharynx to fluid displacement from the legs. First, we demonstrated that displacement of just 340 ml from both legs by LBPP of 40 mm Hg (assuming the fluid shift was twice that of one leg) is sufficient to increase neck circumference. Second, this increase in neck circumference was accompanied by a simultaneous 102% increase in Rph, indicating that the pharynx narrowed. Third, we showed that LBPP of 40 mm Hg had no significant effect on EELV (i.e., functional residual capacity), measured either by respiratory inductance pleythysmography or by multibreath helium dilution, or on blood pressure or heart rate. Thus, the increase in Rph could not be attributed to a decrease in gas volume of the lung (25, 28, 29), nor to reflexes arising from changes in blood pressure (30) or heart rate. Accordingly, the most likely explanation for the increase in Rph was narrowing of the pharyngeal lumen due to a shift of fluid into the nuchal structures, including the great veins and/or peripharyngeal soft tissues. LBPP has been shown to shift blood from the lower body to the upper body and cause an increase of central venous pressure (16, 17, 31). Although in the present study we did not measure central venous pressure, our data showed that LBPP caused both displacement of fluid from the legs and an increase of neck circumference. We measured neck circumference just above the thyroid cartilage, a region that is externally extensible. However, the pharynx and the adjacent segments of the great vessels lie rostral to this region and are encased within a relatively rigid bony envelope consisting of the mandible, maxilla, and the cervical spine (32). Thus, because there is very limited room to distend externally, accumulation of fluid in the jugular and peripharyngeal veins and soft tissues is more likely to distend inwardly and to compress the pharyngeal lumen, thereby increasing Rph. Previous studies have shown that pharyngeal cross-sectional area and Rph are lung volume dependent; a decrease in lung volume is associated with a reduction in pharyngeal caliber and an increase in Rph, and vice versa (28, 33). However, our data are not compatible with this mechanism because there was no significant change in EELV, measured either by respiratory inductance plethysmography or multibreath helium dilution. Rather, there was a tendency for EELV to increase during application of LBPP, which should have reduced, rather than increased, Rph. It has also been shown that topical application of a vasoconstrictor, phenylephrine, to the pharyngeal mucosa can decrease Rph in healthy humans (13), and systemic infusion of the vasodilators papaverine and nitroprusside caused a significant reduction of pharyngeal cross-sectional area in association with an increased thickness of the pharyngeal mucosa in cats (12). These observations suggest that regional vascular tone, which is partially regulated by sympathetic nerve activity, can play a role in altering Rph. A rise in blood pressure due to LBPP might therefore inhibit sympathetic outflow and cause vasodilation. However, this is highly unlikely, because, in our experiments, the amount of fluid displaced by LBPP did not cause any detectible changes in blood pressure or heart rate, and in previous work by others, LBPP of 30 mm Hg did not affect sympathetic vasoconstrictor outflow, blood pressure, or heart rate (16, 17, 34). Therefore, our observation that LBPP increased neck circumference is more in keeping with displacement of fluid into nuchal and peripharyngeal blood vessels and soft tissues as a cause of the increase in Rph. Although obesity is an important risk factor for OSA, regression analyses have shown that body weight only accounts for approximately 20 to 30% of the variability in severity of OSA as quantified by the frequency of apneas and hypopneas during sleep (1–3). Accordingly, other factors must contribute to the pathogenesis of pharyngeal obstruction and severity of OSA. Several studies (35–38) have shown that increased neck circumference is a better predictor of OSA than obesity per se. Thus, an increase in nuchal soft tissue, especially in the peripharyngeal fat pads, could contribute to pharyngeal narrowing. However, compared with the general population, the prevalence of OSA is higher in patients with HF (4–8), even though they have a significantly lower body mass index for a given frequency of obstructive apneas and hypopneas. In addition, obesity is not as great a risk factor for OSA in patients with HF as it is in the general population (39). Thus, factors other than obesity may contribute more to the pathogenesis of pharyngeal obstruction in patients with than in those without HF. Patients with renal failure also have a higher prevalence of OSA than in the general population (9, 10). A factor common to heart and renal failure is fluid overload (40). This excess fluid accumulates in dependent areas. When standing or seated, fluid accumulates in the lower extremities. However, when recumbent, excess fluid in the lower extremities is displaced rostrally. In addition, the degree of caudal to rostral fluid displacement would be greater in hypervolemic patients than in euvolemic subjects when moving from upright to recumbent positions. Indeed, it has been shown that right-sided filling pressures increase progressively in the recumbent position overnight in patients with HF and coronary heart disease (41, 42). Our data show that displacement of a small amount of fluid (340 ml) from the legs is sufficient to cause a 102% increase in Rph in healthy, nonobese subjects. Accordingly, the potential for this physical mechanism to contribute to pharyngeal obstruction during sleep may be greater in hypervolemic than in normovolemic subjects. One limitation of our study is that experiments were conducted during wakefulness. It would not have been feasible for subjects to sleep uninterrupted with antishock trousers in the deflated then inflated state, in addition to having the pharyngeal pressure catheters and face mask in place. It is therefore possible that the present findings may not be reproduced exactly during sleep. However, responses to fluid shift during sleep are unlikely to be qualitatively different. The pharynx narrows and Rph invariably increases at the transition from wakefulness to sleep in patients with OSA and in healthy subjects (32, 43–45). Thus, one would anticipate that a given degree of fluid shift into the neck during sleep would cause an even greater increase in pharyngeal airflow obstruction, because resistance increases inversely to the fourth power of the radius of the pharyngeal lumen. We did not perform sleep studies to ascertain whether subjects had OSA or not. However, it is likely that none or only a very small minority had OSA, because none of our subjects was obese or had a history of habitual snoring or daytime sleepiness. In any case, future experiments will be required to determine whether there are differences to the Rph response to LBPP between subjects with and without OSA. In addition, we did not determine the duration of this effect of LBPP on Rph. It is interesting, however, that Rph increased progressively from baseline to 1 to 5 min after LBPP application. The initial increase may have been due to acute distension of blood vessels in the neck, followed by movement of fluid into the interstitial compartment and lymphatics of the neck and peripharyngeal structures. Further studies will be required to determine the mechanism of this time-related effect, and to assess how long the effects of LBPP on Rph last during more prolonged exposures. We did not measure genioglossus muscle activity. Thus, we cannot rule out the possibility that a reduction in genioglossus activity contributed to the LBPP-induced increase in Rph. However, because we demonstrated that LBPP expelled fluid from the legs, and this was accompanied by an increase in neck circumference, some of this fluid must have shifted to the nuchal structures. Therefore, fluid accumulation in the neck must have contributed to the increase in Rph. Further studies will be required to determine whether LBPP has any effect on genioglossus activity that might affect Rph. In conclusion, our experiments in healthy, nonobese subjects provide novel evidence that a shift of fluid from the lower to the upper body induced by LBPP causes both an increase of neck circumference and a highly significant increase of Rph. Our data favor an increase in the fluid volume of the neck and peripharyngeal structures as the principal mechanism contributing to these effects. Such fluid displacement from the lower extremities to the upper body may increase pharyngeal obstruction in patients predisposed to OSA when moving from the upright to the recumbent position. This may be of particular relevance in edematous states. Further studies will be required to determine whether fluid displacement from the lower to the upper body causes a greater increase in Rph in such patients than in subjects without these conditions, and whether fluid removal or displacement out of the neck in edematous patients reduces Rph.
Originally Published in Press as DOI: 10.1164/rccm.200607-927OC on October 12, 2006 Conflict of Interest Statement: K.-L.C. was supported by a Research Fellowship from ResMed and Respironics, Inc., from July 2005 to June 2006 for $40,000; however, neither company had any influence over the design of the study or its conduct, the analysis of the data, or drafting or approval of the manuscript. Moreover, neither company has any direct financial interest in the findings of the study. C.M.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.S.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.T.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.S.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.D.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form July 10, 2006; accepted in final form September 15, 2006
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