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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have developed a method for measuring the temperature and relative humidity of air prior to and after nasal conditioning and used it to study the effect of treatment with ipratropium bromide on the ability of the nose to condition cold, dry air. We performed randomized, double-blind, placebo-controlled, two-way crossover studies and an open study in nonallergic subjects. The subjects were treated with ipratropium bromide (84 µg) or normal saline solution sprayed into the nasal cavity 15 min before the measurement of nasal conditioning capacity. Cold, dry air was delivered to the nose via a nasal mask, and the temperature and humidity of air were measured before entering and after exiting the nasal cavity. The total water gradient across the nose was calculated and represents nasal conditioning capacity. Ipratropium bromide treatment significantly increased nasal conditioning capacity when compared with saline. Ipratropium bromide led to less reduction in the cold, dry air-induced decrease in the nasal volume (p < 0.05) without affecting the decrease in nasal surface temperature during cold, dry air exposure (p = 0.3). Our data show that ipratropium bromide increases the ability of the nose to condition cold, dry air. Thus, treating rhinitis with ipratropium bromide should not increase the burden for inspired air conditioning on the conducting pulmonary airways.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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One of the primary functions of the nose is to warm and humidify air (1). Potential sources that can provide water for nasal humidification of inspired air are glandular secretions, secretions from the paranasal sinuses, tears via the nasolacrimal duct, secretions from goblet cells, transudation of fluid from the blood vessels, and passive transport against an ionic gradient in the paracellular spaces (2). How altering one of these sources, glandular secretions, affects nasal conditioning is the subject of this study.
In a study by Ingelstedt and Ivstam, the degree of humidification of air in the nose was studied by psychrometer (3). They showed that subcutaneous injection of atropine greatly impaired the humidifying capacity of the nose in healthy subjects. The authors concluded that atropine-inhibitable glandular secretions provide the major source of water for humidification. Ipratropium bromide (ipratropium), a topical anticholinergic agent, has been clearly shown to reduce the amount of watery rhinorrhea in patients with perennial allergic (4) and nonallergic (5) rhinitis and viral infections (6). We questioned whether treating rhinorrhea with topical intranasal ipratropium might worsen the ability of the nose to humidify air. In our studies, we evaluated the contributions of the two major theoretical mechanisms that might lead to the alteration of nasal conditioning capacity: changes in the nasal mucosal surface temperature and in the volume of the nasal cavity (7).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
We recruited healthy volunteers with no history of allergic rhinitis (first study: 8 men and 6 women, ages 21 to 46 yr [mean, 26 yr]; second study: 11 men and 4 women, ages 18 to 35 yr [mean, 22 yr]; third study: 4 men and 3 women, ages 18 to 35 yr [mean, 23 yr]; fourth study: 6 men and 4 women, ages 18 to 35 yr [mean, 25 yr]). Their nonallergic status was confirmed by negative skin puncture testing with a panel of common allergens in the Chicago area. All studies were approved by the Institutional Review Board of the University of Chicago, and written informed consent was obtained from each subject prior to study entry.
Experimental Protocol
We performed two randomized, double-blind, placebo-controlled, two-way crossover studies comparing the effects of ipratropium bromide and saline on the nasal conditioning capacity. The protocols for the first and second studies were similar, with the exception that nasal volume measurement and nasal lavage were also performed in the second study. In both studies, subjects were brought to the laboratory on two separate occasions, acclimatizing for 15 min before initiating treatment. Treatment with ipratropium or saline during the two visits was separated by at least 48 h to eliminate any crossover effect of the drug.
A series of baseline measurements was then performed (Figure 1). Symptoms of nasal congestion, itching, and rhinorrhea were recorded by the subjects. The number of sneezes was counted and recorded by the investigators. The volume of the nasal cavity of the less patent side was measured by acoustic rhinometry. After that, nasal secretions were collected on the same side as the nasal volume measurement and weighed. Then, baseline nasal lavage was performed followed by four nasal lavages to bring albumin levels to a stable baseline. After that, a second baseline nasal lavage was performed.
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Drugs were then administered by the investigators, who were blinded to the type of drug. Two puffs of either 0.06% ipratropium bromide (Atrovent nasal spray: two puffs contain 84 µg of drug) (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) or saline were sprayed into the less patent nostril. After 15 min, a third series of baseline measurements was obtained which included symptoms, nasal cavity volume, and secretion weights. The more patent nostril was chosen for insertion of a probe and was sprayed with three puffs (0.3 ml) of 0.05% oxymetazoline hydrochloride (Nostrilla; Ciba Self-Medication, Inc., Woodbridge, NJ), followed by three puffs (0.3 ml) of 4% topical lidocaine hydrochloride (Roxane Laboratories, Inc., Columbus, OH). Five minutes later, a fourth series of baseline measurements was made, and a probe to measure temperature and relative humidity in the nasopharynx was inserted (see below). The measurement of nasal conditioning was then begun, as described below. After the end of cold, dry air exposure, symptom evaluation, nasal cavity volume measurement, secretion collection, and nasal lavage were repeated.
To investigate whether ipratropium affected the nasal mucosal temperature during nasal conditioning of cold, dry air, we performed a third study in seven normal subjects, all of whom were volunteers who had participated in the second study. In a double-blind, placebo-controlled, two-way crossover manner, subjects were randomized to have treatment with either ipratropium or saline 15 min before cold, dry air exposure. Nasal mucosal temperature was measured before and 15 min after either ipratropium bromide or saline administration. After exposure to cold, dry air at 20 L/min for 8 min, nasal mucosal temperature was measured again.
To investigate the potential effects of the nasal cycle on nasal volume measurement and the effects of oxymetazoline administration on nasal secretion weight, we performed a fourth study in 10 normal subjects, all of whom had also participated in the second study. In this experiment, we administered oxymetazoline into the less patent side and determined whether it affected the nasal volume and secretion weight on the more patent side. The radial pulse was measured after the subjects had rested for 15 min. Then, nasal volume was measured and secretion collected on both sides of the nose. The less patent side as shown by volume measurement was sprayed with three puffs of 0.05% oxymetazoline. After a 5-min wait, radial pulse, nasal volume, and secretion weight measurement were repeated again on both sides.
Nasal Conditioning Measurement
The technique for evaluating the ability of the nose to condition cold, dry air has been described in detail previously (8). In brief, a probe containing a temperature and a humidity sensor was inserted through the nose along the floor of the nasal cavity so that the tip touched the posterior nasopharyngeal wall, and the sensors were suspended in the air stream facing the opposite nostril. The nostril containing the probe was then occluded anteriorly with a wax plug (Mack's Earplug, Mc Keon Products Inc., Pleasant Ridge, MI). A nasal CPAP mask (Respir-onics Inc., Murrysville, PA) was then applied to the face over the probe with head straps. A second probe containing both a temperature and a humidity sensor was inserted into the mask and positioned just outside the nasal cavity.
Cold air at 0% relative humidity was delivered to the patient's nose via the mask at flow rates of 5, 10, and 20 L/min. The air temperature was approximately 19, 10.5, and 0.8° C at 5, 10, and 20 L/min, respectively. The subjects breathed in and out through the mouth. The difference between the water content of air prior to entry into the nose and that in the nasopharynx is the water gradient across the nose; it represents the amount of water evaporated by the nose to condition air, a measure of nasal conditioning.
Collection of Nasal Secretions
Secretions were collected from the anterior nasal septum beyond the mucocutaneous junction of the nostril using filter paper discs (Shandon Inc., Pittsburgh, PA) (9). The weight of secretions generated in 30 s was calculated by subtracting of the precollection from the postcollection weights.
Sneezes and Symptom Scores
The number of sneezes before and after nasal conditioning of cold, dry air was counted and recorded by the investigator. Symptoms of runny and stuffy nose and a combined sensation of itchy nose and throat were graded on a scale as follows: 0 = no symptoms, 1 = very mild, 2 = mild, 3 = moderate, 4 = severe, and 5 = very severe symptoms.
Nasal Lavage
Lavages were performed in the second study by introduction of 2.5 ml
of 37° C lactated Ringer's solution (Baxter Healthcare Corporation,
Deerfield, IL) into each nostril (10). The supernatant was stored at
20° C until assayed for albumin.
Nasal Secretion Osmolality Measurement
Osmolality values were measured in the returned lavage fluids with a Vapro vapor pressure osmometer (Wescor, Inc., Logan, UT). This instrument provides an accuracy of ± 3 mmol/kg-H2O. All measurements were performed in triplicate. The average values are reported.
Albumin Assay
Albumin was measured by an enzyme-linked immunosorbent assay (ELISA) sensitive to 1 ng/ml (11). Samples obtained from the same subject on all visits were always measured in a single assay.
Nasal Mucosal Temperature Measurement
A nasal probe developed for measurement of mucosal surface temperature (12) was calibrated before each use. The probe was inserted into the anterior part of the nasal cavity by means of a nasal speculum and a headlight. The temperature sensor at the end was placed in contact with the nasal mucosa of the anterior part of nasal septum just posterior to the mucocutaneous junction, and it sampled the mucosal temperature at a rate of one measurement per second for 30 s. The mean nasal mucosal temperature was determined. Measurement of nasal mucosal temperature during cold, dry air exposure was performed by advancing of the temperature sensor attached to a small, straight rod through a small opening in the mask.
Nasal Volume Measurement
Nasal volume measurement was performed with an Eccovision Acoustic Rhinometry System (Hood Laboratories, Pembroke, MA). The volume was measured at 0 to 6 cm from the tip of the rhinometry probe. Each measurement was performed in triplicate, and the average values are reported.
Statistical Analysis
For the water gradient, statistical analysis was performed by use of parametric statistics. This choice is based on the normal distribution of data from prior experience (8). The total water gradient was calculated as the sum of the nasal water gradient during each of three flow rates tested (5, 10, and 20 L/min). Repeated measurements were compared by analysis of variance (ANOVA), and post-hoc analysis was performed with Fisher's test of least significant difference. Comparison of results within the same group of subjects was done by paired t test.
For other parameters, nonparametric statistics was used for analysis because the data were not normally distributed. Repeated measurements were first analyzed by Friedman ANOVA, and, if a significant difference was found, post-hoc analysis between two selected time points was performed with the Wilcoxon signed rank test.
Correlations were performed by the Spearman Rank method. A p value (two-tailed) < 0.05 was considered to indicate significance. WG values are presented as mean ± SEM. Other parameters are presented as median, with the 25th-75th percentiles in parentheses.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the first study, after ipratropium bromide administration, increasing the cold, dry air flow rate progressively increased the water gradient (Figure 2). There were significant differences among water gradient values at all three flow rates (p < 0.001 for each comparison). After saline administration, increasing the cold, dry air flow rate also progressively increased the water gradient, but to a lesser extent than that after ipratropium. Water gradient values obtained at 10 (p < 0.05) and 20 L/min (p < 0.001) as well as the total water gradient (p < 0.001) were greater after ipratropium.
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During the second study, ipratropium similarly increased
water gradient values after 10 or 20 L/min (p < 0.05 each) and
the total water gradient (p < 0.05), when compared with values after saline (Figure 3). Neither saline nor ipratropium administration affected nasal volume. In contrast, after oxymetazoline and lidocaine administration in the more patent side,
the nasal volume of the other side (less patent side) increased
significantly in both groups (p < 0.001). There was also a significant reduction in nasal volume after cold, dry air exposure
in both groups (p < 0.001). Ipratropium treatment, however,
was associated with a smaller reduction in nasal volume after
cold, dry air exposure (ipratropium: 3.3 [3.6, 1.9] cm3
versus saline: 3.4 [4.5, 2.8] cm3; p < 0.05) (Figure 4).
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p < 0.01 versus B1; Ipratropium led to a significant reduction in secretion weight (p < 0.01) compared with the baseline. After oxymetazoline and lidocaine administration in the more patent side, the secretion weight obtained from the other side (less patent side) increased significantly in the saline group (p < 0.05) and decreased significantly in the ipratropium group (p < 0.05). There was also a significant increase in nasal secretion weight after cold, dry air exposure in both groups (p < 0.001). The magnitude of the increased secretion weight after cold, dry air exposure (saline: 8.7 ± 1.9 mg, ipratropium: 14.1 ± 2.5 mg) was greater than that of the increased nasal secretion weight after oxymetazoline and lidocaine administration in the saline group (2.3 ± 1.2 mg), or that of the decreased nasal secretion weight after oxymetazoline and lidocaine administration in the ipratropium group (1.1 ± 0.5 mg). Ipratropium led to a smaller increase in nasal secretion weight after cold, dry air exposure when compared with saline treatment (ipratropium: 5.6 [3-12.5] mg versus saline: 12.7 [8-18] mg; p < 0.05) (Figure 4).
There were significant increases in rhinorrhea scores (ipratropium: p < 0.01, saline: p < 0.001) and congestion scores (ipratropium: p < 0.05, saline: p < 0.001) after cold, dry air exposure compared with baseline in both groups. Ipratropium led to a smaller increase in rhinorrhea scores after cold, dry air exposure when compared with saline treatment (ipratropium: 0 [0-2] versus saline: 1 [1-2]; p < 0.01) whereas there were no significant differences in the net change of congestion scores after cold, dry air exposure between the two groups (p = 0.5).
The nasal secretion osmolality increased significantly after
cold, dry air exposure in both groups (p < 0.001). A significant attenuation of the cold, dry air-induced increase in osmolality was found in the ipratropium bromide group (ipratropium:
5 [3.3-5.7] mmol/kg-H2O versus saline: 7.7 [5-10] mmol/kg-H2O; p < 0.05). There was a significant increase in albumin
levels only after cold dry air exposure when subjects were
treated with ipratropium (p < 0.01). There was a significant
increase in the net change of albumin levels after cold, dry air
exposure in the ipratropium group (ipratropium: 28.3 [2.3-
39.5] versus saline: 12.2 [0.2, 23.5]; p < 0.05) (Figure 5). In
the second study, there was no significant correlation between
the total water gradient and measures of albumin or nasal volume
in both groups (p > 0.05 all).
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In the third study, neither ipratropium nor saline affected
the nasal mucosal temperature when compared with the baseline temperature. Nasal mucosal temperature after administration of both drugs decreased significantly after cold, dry air
exposure (p < 0.05), but there were no significant differences
in the cold, dry air-induced decrease in nasal mucosal temp-erature between the two groups (ipratropium: 7.9 [9,
6.3]° C versus saline: 8.2 [9.9, 7.4]° C; p = 0.3) (Figure 6).
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In the fourth study, there were no significant differences in
radial pulse before and after oxymetazoline administration (p = 0.2) (Table 1). Nasal volume increased significantly in the ipsilateral, less patent side (p < 0.01) and decreased significantly in the contralateral, more patent side (p < 0.01) after oxymetazoline administration. There were no significant differences in
nasal secretion weights in the ipsilateral, less patent side (p = 0.6), but there was a significant increase in secretion weight in the contralateral, more patent side (p < 0.05) after oxymetazoline administration (Table 1). There was no significant correlation between the increase in secretion weight and the decrease in
nasal volume in the more patent side (r = 0.1, p = 0.79).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The nasal mucosa contains numerous seromucinous glands (13). Secretions from these glands are thought to contribute to humidification of inspired air (2), as do secretions from other sources, including the vast network of fenestrated capillaries found immediately underneath the respiratory epithelium (14). The cholinergic nervous system is primarily responsible for the glandular secretory nasal response (15, 16).
Ipratropium, an anticholinergic drug, has been used clinically for reduction of rhinorrhea. Based on a prior report (3), we were concerned that ipratropium, while decreasing the secretory response, might worsen the ability of the nose to warm and humidify air. Our data, however, showed that treatment with ipratropium significantly increased the ability of the nose to condition cold, dry air. The clinical relevance of this change is unknown. Although it is intuitive that improving conditioning would be beneficial, this has not been proven. In contrast, worsening of conditioning shifts the need to condition air to the lower airway. Such a shift could have adverse consequences. Our results clearly indicate that the latter does not happen after ipratropium.
There have been few investigations of the effect of anticholinergic agents on nasal conditioning. Ingelstedt and Ivstam (3) insufflated dry air at a flow rate of 8 L/min for 10 min through one nostril and out through the other. The absolute humidity in subjects treated with atropine sulfate (1 mg subcutaneously) was significantly lower than that of normal subjects. The decrease in humidifying capacity in their study compared with ours could be related to the different dose or route of administration, or the technique of nasal conditioning measurement, i.e., they directed air counter to normal mucosal temperature gradient. Kumlien and Drettner (18) measured the nasal conditioning capacity in 16 healthy volunteers after application of 0.06 mg of ipratropium and showed no significant differences compared with no treatment. Consistent with Kumlien and Drettner's finding, our results demonstrated no significant differences in nasal conditioning after ipratropium and saline administration at a flow rate of 5 L/min. Our studies, however, showed significant differences at 10 and 20 L/ min. The increasing flow rates led to the need for more water evaporation such as occurs with mild to moderate exercise, emphasizing the need to stress a system for full appreciation of the influence of agents on function.
Theoretically, the two most important parameters affecting nasal conditioning are nasal mucosal temperature and the volume of the nasal cavity (7). The nasal volume decreased significantly after cold, dry air exposure in both groups, and the congestion scores paralleled this finding, consistent with previous reports (19). Our results showed that ipratropium treatment significantly reduced the cold, dry air-induced decrease in the nasal volume compared with saline treatment, although the difference was small. The impact of such a change on conditioning is unknown. There were no significant differences in the net change in the congestion score after cold, dry air exposure in both groups. This inconsistency is probably related to the higher sensitivity of the objective measurement of nasal volume compared with the subjective measurement of nasal congestion. The dissociation of these two parameters is seen in other nasal responses such as after inhalation of menthol (22) or after surgical reduction of enlarged turbinates (23, 24).
The mechanism by which ipratropium prevents a decrease in nasal volume after exposure to cold, dry air is unknown. Vasodilation of the nasal vascular bed in response to cold, dry air may be mediated by the parasympathetic system. In support of this hypothesis, vasodilation of nasal vessels in cats can be induced with electrical stimulation of parasympathetic fibers or with exogenous acetylcholine and can be partially inhibited by atropine (25, 26). The presence of muscarinic receptors on capacitance vessels suggests that a parasympathetic cholinergic reflex would also increase nasal blood flow, which would lead to filling of sinusoids and to decreasing airway patency (27). Ipratropium could reduce this parasympathetic activation by blocking these muscarinic receptors and therefore attenuate the reduction in nasal volume after cold, dry air exposure. Theoretically, this end point should provide less nasal surface area for conditioning of cold, dry air and hence lead to a decreased nasal conditioning capacity after ipratropium administration, in contrast to our finding. This conflict suggests that there must be other mechanisms responsible for the observed increase in nasal conditioning after ipratropium treatment.
The other theoretically important parameter determining the nasal conditioning is nasal mucosal temperature. Our results demonstrated that nasal mucosal temperature decreased significantly during inhalation of cold, dry air, and there were no significant changes in nasal mucosal temperature at baseline or after cold, dry air between ipratropium and saline. One might conclude that a change in the nasal mucosal temperature is probably not responsible for the increased nasal conditioning observed after ipratropium administration. However, more water was evaporated during the same exposure in the ipratropium group, implying that more heat was lost and hence more heat through increased blood flow to the subepithelial capillary network had to be provided to the mucosa to maintain it at the same temperature at the end of both treatments. We speculate that subepithelial superficial capillary blood flow in the ipratropium group was higher than that in the saline group to maintain the same nasal surface temperature.
Nasal secretion osmolality in both ipratropium bromide and saline groups increased significantly from baseline after cold, dry air exposure, in agreement with previous studies (28). Increased osmolality could trigger mast cells to release more histamine, which would increase superficial blood flow and increase vascular permeability. Our results, however, demonstrated that ipratropium led to a significant reduction in the cold, dry air-induced increase in nasal secretion osmolality compared with saline. This apparent paradoxical finding may be explained by the observation of Cruz and coworkers that the osmolality of undiluted nasal secretions was higher than that of serum (29). Therefore, the ipratropium-related reduction of the osmolality of the returned lavage fluids after cold, dry air exposure may reflect the inhibition of hyperosmolar secretions from nasal glands. This finding is consistent with the observation that intranasal application of atropine significantly reduced the osmolality of recovered lavage fluids after cold, dry air exposure as compared with placebo (28). The effects on glands, combined with the higher water loss during ipratropium treatment, suggests the following mechanism to explain our observations: more movement of lower-osmolar fluid from vessels mixed with less hyperosmolar glandular secretions during exposure to cold, dry air after treatment with ipratropium. This hypothesis is supported by our measurements of albumin levels.
Albumin levels in returned lavage fluids increased significantly after cold, dry air exposure in the ipratropium group. Theoretically, inhalation of cold, dry air causes drying of the nasal mucosa, hyperosmolality of nasal secretion, and then mast cell activation. Thus, an increase in albumin levels after cold, dry air exposure may be caused by a direct effect of histamine on H1-receptors on superficial blood vessels, resulting in an increase in vascular permeability. The increase in albumin levels in the ipratropium group could reflect an increase in superficial capillary blood flow secondary to increased histamine release.
Interestingly, the contralateral nasal volume increased significantly after ipsilateral oxymetazoline administration. We administered this drug into the more patent side, which was selected for probe insertion. We hypothesized that this finding might be the result of variations of the nasal cycle or systemic absorption of oxymetazoline. We tested this hypothesis and found that there were no significant differences in radial pulse before and after oxymetazoline administration, suggesting that systemic absorption was unlikely. After oxymetazoline administration into the less patent nostril, there was a significant reciprocal reduction in the volume of the more patent side. Flanagan and Eccles (31) also demonstrated that decongestion of the less patent side was accompanied by congestion of the more patent side. This suggests that the increase in nasal volume of the contralateral side in response to oxymetazoline administration is probably caused by the nasal cycle.
In summary, we have shown that ipratropium, which is effective for the treatment of rhinorrhea, increased the ability of the nose to condition air. This effect is probably related to an increase in superficial nasal mucosal blood flow rather than to changes in nasal volume. Our results clearly indicate that blocking nasal glands does not impair the ability to warm and humidify air, suggesting that there are other sources providing fluid for the humidification process and emphasizing the complex responses of a physiological system like the nose that cannot be predicted a priori by a theoretical model. The information that ipratropium does not impair the nasal conditioning is clinically useful in the treatment of patients with rhinorrhea and asthma, because this agent leads to better conditioned air and should not adversely affect the lower airway. Additionally, we speculate that the mechanisms proposed in this study may partially explain the beneficial effect of the use of this agent in the treatment of asthma.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Robert M. Naclerio, M.D., Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, 5841 S. Maryland Ave., MC 1035, Chicago, IL 60637. E-mail: rnacleri{at}surgery.bsd.uchicago.edu
(Received in original form December 13, 1999 and in revised form March 28, 2000).
Acknowledgments: Supported by Grants DC 02714 and AI 45583 from the National Institutes of Health, Bethesda, Maryland, and a grant-in-aid from Boehringer Ingelheim Pharmaceuticals, Inc.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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