The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients

Otolaryngology–Head and Neck Surgery (2007) 137, 815-821

ORIGINAL RESEARCH—SINONASAL DISORDERS

The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients Garrett Hauptman, MD and Matthew W. Ryan, MD, Galveston and Dallas, TX OBJECTIVE: To compare the effect of two saline nasal sprays on nasal patency and mucociliary clearance in patients with rhinosinusitis. STUDY DESIGN: Randomized double-blind trial. SUBJECTS AND METHODS: Eighty patients with rhinosinusitis at a tertiary care academic center had nasal patency and mucociliary clearance measured. Each patient was then treated with either physiological or hypertonic saline. Nasal patency and mucociliary clearance measurements were repeated after treatment. Subjective evaluation was also performed. RESULTS: Both solutions improved saccharine clearance times (P ⬍ 0.0001). Buffered physiological saline significantly affected nasal airway patency (P ⫽ 0.006). Both solutions improved symptoms of nasal stuffiness (P ⬍ 0.0001) and nasal obstruction (P ⬍ 0.0001). Buffered hypertonic saline caused increased nasal burning/ irritation compared with buffered physiological saline (P ⬍ 0.0001). CONCLUSIONS: Buffered physiological and buffered hypertonic saline nasal sprays both improve mucociliary clearance, which is beneficial for treatment of rhinosinusitis. Additionally, buffered physiological saline improves nasal airway patency, whereas buffered hypertonic saline has no effect. Both solutions provide symptomatic relief, but buffered hypertonic saline is more irritating. © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.

T

he use of nasal irrigation dates back centuries. One of the earliest examples is the use of nasal irrigation with a hypertonic solution as part of purification routines in preparation for yoga. Western medicine had adopted this practice by the 19th century. In 1895 an editorial appeared in the British Medical Journal describing the “civilized nose” as “one of the dirtiest organs in the body.” According to this article, to cleanse the nose one was “to plunge the face into a basin of clean water, cold or tepid, and take slight sniffs, in and out, while under water.”1 For more than a century Western physicians have recommended nasal irrigation for treatment of sinonasal disease and after sinonasal surgery. The goals of this treatment are to clear secretions, debris, and crusts, reduce risk of postoperative mucosal adhesions, and expedite mucosal healing. The objective and subjective efficacy of saline irrigation for the treatment of sinonasal disease has been demonstrated, and saline irriga-

tions are increasingly used to treat rhinosinusitis.2 There are still significant questions, however, about the optimal pH, salinity, and content of these intranasal saline treatments,3 especially since previous studies have shown that hypertonic saline causes more burning than physiological saline.4 The effect of buffered physiological saline spray and buffered hypertonic spray on nasal mucociliary clearance in normal healthy subjects has been studied by Talbot et al.5 They showed that buffered hypertonic saline nasal irrigation improved mucociliary clearance, whereas buffered physiological saline had no effect on mucociliary clearance. Additionally, these investigators posited that hypertonic saline might have the added beneficial effect of decongesting the nose through an osmotic mechanism. These issues were reexamined in a study of healthy volunteers by Keojampa et al,6 which showed improved mucociliary clearance with both solutions (although buffered hypertonic saline had a greater effect). In that study, acoustic rhinometry showed no change in the nasal airway dimensions with instillation of either solution, raising questions about the comparative benefit of hypertonic saline. The purpose of the current study is to provide further information about the effects of different saline solutions on nasal physiology by comparing the effect of buffered physiological saline and buffered hypertonic saline sprays on mucociliary clearance time (as assessed by the saccharine clearance method) and on nasal cavity dimensions (as assessed by acoustic rhinometry) in patients with rhinosinusitis (the primary outcome measures). Additionally, the acute effects of saline instillation on symptoms of nasal stuffiness, nasal obstruction, and nasal burning/ irritation were assessed (secondary outcome measures). Our hypotheses were that hypertonic saline does not affect nasal patency, that both solutions improve mucociliary clearance, and that both solutions provide some measure of symptomatic relief.

METHODS This was a double-blind, randomized study of the acute effects of two saline nasal sprays on nasal physiology in

Received April 11, 2007; revised July 17, 2007; accepted July 25, 2007.

0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2007.07.034

816

Otolaryngology–Head and Neck Surgery, Vol 137, No 5, November 2007

patients with suspected rhinosinusitis. Informed consent was obtained from all subjects, and this study was approved by the University of Texas Medical Branch Institutional Review Board for research involving human subjects. Eighty patient volunteers were included in this study. These subjects were recruited from the otolaryngology clinic patient population at the University of Texas Medical Branch from November 2005 to January 2006. The first inclusion criterion was subjective rhinosinusitis of any duration, based on the major and minor symptoms of rhinosinusitis promulgated by the Rhinosinusitis Task Force and others.7 For the purposes of this study, objective evidence of rhinosinusitis via anterior rhinoscopy, nasal endoscopy, and imaging was not required for enrollment. One of the authors (G.H). interviewed each potential subject using the major and minor criteria of rhinosinusitis. Only those individuals who met criteria for a “probable diagnosis” of rhinosinusitis on the basis of symptoms were invited to participate in the study. The second inclusion criterion was a minimum Sinonasal Outcome Test-20 (SNOT-20) score of 20. Twenty was chosen as the minimum score on the basis of the findings reported by Piccirillo et al8 in their work validating the SNOT-20, which is a valid outcome measure that describes the health burden for patients with rhinosinusitis. The scores for the SNOT-20 can range from 0 to 100, with higher scores indicating more severe symptoms. Initial validation studies of this instrument in a group of patients with rhinosinusitis yielded a mean SNOT-20 score of 38 with a standard deviation of 18. One standard deviation below the mean is 20, which provided the rationale behind the selection of a minimum score of 20 for inclusion in this study. The exclusion criteria were past history of nasal and/or sinus surgery and the use of medication to treat rhinosinusitis symptoms delivered nasally or orally including decongestants, antihistamines, and steroids.

Study Procedures After initial screening to determine eligibility, each patient received a pretest that asked them to rate their current symptoms of nasal stuffiness and nasal obstruction on a scale of 1 to 10 (Likert scale). One was assigned as being unnoticeable and not troublesome, whereas 10 was assigned as being very noticeable and very bothersome. Nasal patency was then measured with an acoustic rhinometer from Rhinometrics (Interacoustics, Assens, Denmark) with the use of the Rhinoscan software system. Measurements were obtained on the side of the nose in which the patient felt the symptoms were worse. Either a regularor large-sized nose adapter was selected on the basis of the external nostril dimensions of the patient. A water-soluble gel was applied to the outer rim of the nose adapter to ensure a soundproof seal between the nose and the rhinometer. Three separate measurements were obtained to ensure reproducibility. The mean and standard deviation of these measurements were calculated. The data recorded were the minimal cross-sectional area (MCA) at two different points. MCA1 was measured at a distance between 0 mm and 22 mm,

and MCA2 was measured at a distance between 22 mm and 54 mm, where 0 mm is the point at which the nose adapter contacts the nostril. Increased values at MCA1 and MCA2 denote enlarged nasal airway dimensions. Mucociliary clearance was then measured by the saccharine clearance test method. The patient’s nose was examined with the use of a nasal speculum and a headlight while the patient was seated in an upright position. An ear curette was used to place a small piece of saccharine on the medial aspect of the inferior turbinate approximately 1 cm posterior to the nasal vestibule. Patients were instructed to avoid sniffing or sneezing during this test. The mucociliary clearance time was recorded as the patient’s first perception of a sweet taste. At this point, after the performance of baseline studies, research subjects were randomly assigned to either buffered physiological saline or buffered hypertonic saline. Randomization was performed with the use of a computerized random number generator. An independent study pharmacist dispensed buffered physiological or buffered hypertonic saline (3%) according to the computer-generated randomization list. This technique resulted in both the patient and the investigator being blinded to which solution was administered. One milliliter of solution was delivered to the more symptomatic nasal cavity in each patient with a metereddose nasal spray bottle (100 ␮L per actuation). After 10 minutes mucociliary clearance time was again assessed. Following this step, acoustic rhinometry was repeated. A posttest was given to each patient after the second set of acoustic rhinometry measurements was completed. Once again, the patient was asked to rate the current symptoms of nasal stuffiness and nasal obstruction on a scale of 1 to 10. Additionally, a third component was added to the posttest to assess symptoms of burning/nasal irritation. On the scales, 1 was assigned as being unnoticeable and not troublesome, whereas 10 was assigned as being very noticeable and very bothersome. Only nasal stuffiness, nasal obstruction, and nasal burning/irritation were assessed in these pretests and posttests. These instantaneous symptom scores have not been validated and serve merely to assess the acute symptomatic effects of nasal saline administration. The chi-square test, the Fisher exact test, and the MannWhitney U test were used to test for statistical significance. Both mucociliary clearance time data and cross-sectional area data obtained before and after treatment with either saline solution were compared by using the Wilcoxon signed rank test and the Mann-Whitney U test. The results of the pretest and posttest Likert scale were compared by using the Wilcoxon signed rank test and the Mann-Whitney U test.

Role of the Funding Source The American Academy of Otolaryngic Allergy had no role in the study design, collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the paper.

Hauptman and Ryan

The effect of saline solutions on nasal patency and. . .

817

Table 1 SNOT-20 scores and demographic parameters of the 2 groups Physiological

Age

Gender Male Female Race White Black Hispanic Asian

SNOT-20

Hypertonic

Mean ⫾ SE

Range

Mean ⫾ SE

Range

P value

35 ⫾ 2

23-63

37 ⫾ 2

21-64

0.26

Number

Percentage

Number

Percentage

12 28

15% 35%

15 25

19% 31%

0.48

33 1 2 4

41% 1% 3% 5%

32 2 3 3

40% 3% 4% 4%

0.82

Mean ⫾ SE

Range

Mean ⫾ SE

Range

P value

33 ⫾ 2

20-67

37 ⫾ 2

21-68

0.15

SNOT-20, Sinonasal Outcome Test-20.

RESULTS Statistical analysis was performed to test if the randomization technique was successful. The results are summarized in Table 1. Demographic parameters and SNOT-20 scores were balanced between the two groups. Mucociliary clearance results measured by the saccharine clearance test method in both pretreatment and posttreatment are summarized in Table 2 and depicted graphically in Figure 1. Both solutions improved saccharine clearance times. The decrease in mucociliary clearance time was larger with buffered hypertonic saline (178 seconds versus 121 seconds; Fig 1). An improvement in mucociliary clearance was observed in 39 of 40 (98%) patients administered buffered physiological saline and 38 of 40 (95%) patients administered buffered hypertonic saline. Buffered physiological saline significantly affected nasal airway patency, whereas buffered hypertonic saline had no effect on nasal patency. Nasal patency was observed to increase by 6.7 percent at MCA1 and by 20.8 percent at MCA2 with buffered physiological saline, whereas buffered hypertonic saline caused a decrease in nasal patency by 1.2 percent at MCA1 and by 4.3 percent at MCA2. Of these 4 changes, only the MCA2 of buffered physiological saline reached statistical significance. These results are summarized in Table 2 and depicted graphically in Figure 2. Subjective assessment of symptoms (nasal stuffiness, nasal obstruction, and burning) was performed. Both solutions improved symptoms of nasal stuffiness and nasal obstruction. Buffered hypertonic saline caused increased nasal burning/irritation compared with buffered physiological saline. These results are summarized in Table 3.

There was poor correlation between subjective symptoms as assessed with the SNOT-20 and objective measures such as mucociliary clearance time and nasal cross-sectional area. The Pearson correlation coefficient (r) for SNOT-20 score and mucociliary clearance time was 0.07. The r value for SNOT-20 and MCA1 was – 0.10 and for MCA2 was – 0.09. These results are similar to previous findings from our group that showed no correlation between mucociliary clearance time and SNOT-20 scores.9

DISCUSSION Nasal saline sprays and irrigations are commonly employed treatments for rhinosinusitis. Saline irrigation is also one of the most widely prescribed treatments in postoperative care following endoscopic sinus surgery. Hypertonic saline in particular has been promoted as an agent that improves mucociliary clearance and increases nasal patency secondary to a decrease in nasal mucosa edema.5 A physician’s prescription for buffered physiological saline or buffered hypertonic saline is often based on anecdotal evidence. The experimental results that we present may assist physicians in choosing which solution to prescribe for nasal irrigation or sprays. The results observed in this study showed an improvement in mucociliary clearance time with both buffered physiological saline and buffered hypertonic saline. Since both solutions result in improvement of mucociliary clearance time, the decision of which solution to use is not clarified on the basis of this measurement alone. However, the difference in MCA2 between groups was statistically and also, we believe, clinically signifi-

818

Otolaryngology–Head and Neck Surgery, Vol 137, No 5, November 2007

Table 2 Mucociliary clearance times and minimal cross-sectional areas for the two groups Baseline mucociliary clearance times and minimal cross-sectional areas Physiological (mean ⫾ SE)

Hypertonic (mean ⫾ SE)

P value

829 ⫾ 27 0.49 ⫾ 0.03 0.66 ⫾ 0.05

891 ⫾ 34 0.53 ⫾ 0.02 0.67 ⫾ 0.05

0.10 0.28 0.94

Mucociliary clearance (s) Cross-sectional area: MCA1 (cm2) Cross-sectional area: MCA2 (cm2)

Changes in mucociliary clearance time and cross-sectional areas Physiological

Mucociliary clearance (s) Cross-sectional area: MCA1 (cm2) Cross-sectional area: MCA2 (cm2)

Before treatment (mean ⫾ SE)

After treatment (mean ⫾ SE)

829 ⫾ 27

Hypertonic

P value

Before treatment (mean ⫾ SE)

After treatment (mean ⫾ SE)

P value

702 ⫾ 21

⬍0.001

891 ⫾ 34

713 ⫾ 23

⬍0.001

0.49 ⫾ 0.03

0.52 ⫾ 0.03

0.09

0.53 ⫾ 0.02

0.51 ⫾ 0.02

0.58

0.66 ⫾ 0.05

0.78 ⫾ 0.06

0.01

0.67 ⫾ 0.05

0.63 ⫾ 0.05

0.30

Comparison of changes from baseline

Mucociliary clearance Absolute ⌬ (s) Relative ⌬ (% change) Cross-sectional area: MCA1 Absolute ⌬ (cm2) Relative ⌬ (% change) Cross-sectional area: MCA2 Absolute ⌬ (cm2) Relative ⌬ (% change)

Physiological (mean ⫾ SE)

Hypertonic (mean ⫾ SE)

P value

121 ⫾ 25 12.8% ⫾ 2.3%

178 ⫾ 34 18.0% ⫾ 2.2%

0.002 0.003

0.02 ⫾ 0.01 6.7% ⫾ 3.5%

⫺0.01 ⫾ 0.02 ⫺1.2% ⫾ 3.3%

0.097 0.138

0.11 ⫾ 0.03 20.8% ⫾ 6.6%

⫺0.04 ⫾ 0.03 ⫺4.3% ⫾ 3.6%

0.004 0.004

MCA1, minimal cross-sectional area at 0-22 mm; MCA2, minimal cross-sectional area at 22-54 mm, where 0 mm is the point at which the nose adapter contacts the nostril.

cant. This finding means that buffered physiological saline significantly increases nasal patency at MCA2 in comparison with the pretreatment condition and in com-

Figure 1

parison with buffered hypertonic saline patients after treatment. A lack of statistically significant change at MCA1 may be due to the architecture and tissue compo-

Mucociliary clearance time before and after treatment.

Hauptman and Ryan

The effect of saline solutions on nasal patency and. . .

Figure 2

819

Average minimal cross-sectional area before and after treatment.

sition of the nasal cavity at that defined range of distance (0-22 mm). Although the effects of buffered hypertonic saline did not reach statistical significance with regard to crosssectional area, the trend observed should be discussed. A study performed by Baraniuk et al10 showed a decrease in the minimal cross-sectional area (ie, a congesting effect) in normal healthy subjects treated with buffered hypertonic nasal saline irrigation. At first glance, this result might seem surprising if the hypothesized difference between the two solutions is based solely on osmotic forces and concentration gradients. Clearly, more factors play a role in this response. The fact that administration of hypertonic saline causes nasal discomfort to a greater extent than physiological saline is well-described in the literature and was confirmed in this study. The sequelae of this discomfort have been described as obstruction, rhinorrhea, and increased glandular secretion.11-13 At the biochemical level, nasal mucosal irritation produces a transient increase in inflammatory mediators including peptide leukotrienes (leukotriene C4, leukotriene D4, leukotriene E4), prostaglandin E2, and thromboxane B2,

lasting approximately 1 hour.14 Additionally, the induction of pain and the release of the neurotransmitter substance P suggest that neurogenic mechanisms are activated. In human skin, neurogenic responses include the triple response of Lewis (flush: capillary dilation; flare: arteriolar dilation; and wheal: exudation and edema). Extrapolation of this logic would predict that hypertonic saline–induced neural responses will lead to vascular change causing swelling and obstruction.13 The “neurovascular” hypothesis has been tested by human nasal provocation, making use of acoustic rhinometry. Changes in nasal volume were hypothesized as being secondary to either 1) increased mucosal thickening caused by venous sinusoid engorgement, or plasma extravasation and superficial mucosal edema, and/or 2) increased mucous volume due to plasma exudation or glandular exocytosis from serous and mucous cells.15 Superficial mucosal dilation analogous to cutaneous flare may be stimulated. Further studies including measurement of superficial blood flow in the nasal mucosa are necessary to evaluate this proposed mechanism.10,16

Table 3 Symptom assessment: Likert scale results comparing buffered physiological and buffered hypertonic saline groups

Likert scale Nasal stuffiness Physiological Hypertonic Nasal obstruction Physiological Hypertonic Burning/irritation* Physiological Hypertonic

Pretest (mean ⫾ SE)

Posttest (mean ⫾ SE)

P value

5.9 ⫾ 0.3 6.6 ⫾ 0.3

3.7 ⫾ 0.3 4.1 ⫾ 0.3

⬍0.001 ⬍0.001

5.9 ⫾ 0.4 6.7 ⫾ 0.3

3.1 ⫾ 0.3 3.9 ⫾ 0.3

⬍0.001 ⬍0.001 P value ⬍0.001

*Burning/irritation was assessed only after treatment.

1.3 ⫾ 0.1 2.7 ⫾ 0.2

820

Otolaryngology–Head and Neck Surgery, Vol 137, No 5, November 2007

Likert scales are commonly employed in health care to quantify symptom severity. The results of the Likert scale used in this study showed significant symptomatic improvement of nasal stuffiness and nasal obstruction in both groups. No symptomatic difference was noted between the groups. However, use of the buffered hypertonic nasal saline elicited a higher score for burning/irritation compared with buffered physiological nasal saline. This effect has previously been reported by multiple authors.11-14 Patient comfort should be taken into account when nasal saline solutions are prescribed because this factor will likely have an impact on compliance. Potential sources of error in this study could come from saccharine clearance times and acoustic rhinometry measurements. Obtaining accurate saccharine clearance times for comparison before and after treatment depend on the investigator’s ability to place the saccharine in the same spot on the inferior turbinate. The patient’s responsibility lies in following instructions and notifying the investigator when they perceive a sweet taste. This study minimized potential bias and variability by having one investigator perform all of the experiments on the subjects, blinding both the investigator and the subject to the solution content, and observing the subjects until completion of the mucociliary clearance measurement. Previous studies have reported changes in mucociliary clearance patterns based on the nasal cycle.17,18 To limit the impact of the nasal cycle, we took measurements on the side that was subjectively more obstructed and repeated the measurements in the same nasal cavity side after treatment. Acoustic rhinometry has several factors that limit accuracy. Some of the major inherent problems are the overestimation of cross-sectional area in the posterior nasal cavity and the inability to measure accurately beyond narrow spaces. The MCA1 and MCA2 measured are within a set distance into the nose ranging between 0 mm and 54 mm which corresponds to the distance where acoustic rhinometry is most accurate. Additionally, measurements were repeated three times to ensure reproducibility. Sound loss between the nostril, paranasal sinuses, and acoustic probe can negatively affect the accuracy of measurements of more distal aspects of the nasal cavity. Sound loss between the nostril and the acoustic probe was minimized by selecting an appropriately sized adapter and applying a thin layer of gel to the adapter as an acoustic seal. A final limitation of this study is that the time at which the second set of acoustic rhinometer measurements was taken was not uniform among all of the subjects because the second measurement of mucociliary clearance preceded the second set of acoustic rhinometer measurements. As a result, the second set of acoustic rhinometer measurements occurred at 10 minutes plus the subject’s mucociliary clearance time (10 minutes ⫹ mucociliary clearance time). This could impact results because the

response of nasal mucosa to stimuli is time-dependent on a biochemical level.14 Finally, this study measured only the acute effects of nasal saline instillation. Clinical trials that evaluate the effects of these solutions after prolonged use could yield additional useful information for those seeking the ideal saline nasal spray.

CONCLUSION In this study of subjects with rhinosinusitis, both buffered physiological and buffered hypertonic saline nasal spray significantly improved mucociliary clearance. The magnitude of this effect was greater with buffered hypertonic saline nasal spray. Nasal patency was increased with buffered physiological saline nasal spray. Buffered hypertonic saline nasal spray did not change nasal patency. Subjectively, both solutions improved symptoms of nasal stuffiness and nasal obstruction. Buffered hypertonic saline nasal spray was associated with a higher level of burning and irritation. All of these factors should be taken into account when prescribing saline nasal sprays and irrigations to patients with rhinosinusitis.

ACKNOWLEDGMENTS Cheryl Langford, MA, editing and preparation of the manuscript; the American Academy of Otolaryngic Allergy, funding for this study.

AUTHOR INFORMATION From the Department of Otolaryngology, The University of Texas Medical Branch (Dr Hauptman), Galveston, and the Department of Otolaryngology, The University of Texas Southwestern Medical Center (Dr Ryan), Dallas. Presented at the Annual Meeting of the American Academy of Otolaryngic Allergy September 15, 2006, Toronto, Canada. Corresponding author: Matthew W. Ryan, MD, Department of Otolaryngology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9035. E-mail address: [email protected].

AUTHOR CONTRIBUTIONS Garrett Hauptman, data collection, data analysis, writing; Matthew W. Ryan, study design, data analysis, writer.

FINANCIAL DISCLOSURES Garrett Hauptman, none. Matthew W. Ryan, consultant for Alcon, Inc. Supported by a ROAD Scholar grant from the American Academy of Otolaryngic Allergy.

Hauptman and Ryan

The effect of saline solutions on nasal patency and. . .

REFERENCES 1. To blow or wash? BMJ 1895;Nov:213. 2. Rabago D, Barnet B, Marchband L, et al. Qualitative aspects of nasal irrigation use by patients with chronic sinus disease in a multimethod study. Ann Fam Med 2006;4:295–301. 3. Scheid DC. Nasal irrigation to treat acute bacterial rhinosinusitis, in reply. Am Fam Physician 2005;72(9):1661–3. 4. Adam P, Stiffman M, Blake R. A clinical trial of hypertonic saline nasal spray in subjects with the common cold or rhinosinusitis. Arch Fam Med 1998;7:39 – 43. 5. Talbot AR, Herr TM, Parsons DS. Mucociliary clearance and buffered hypertonic saline solution. Laryngoscope 1997;107:500 –3. 6. Keojampa BK, Nguyen MH, Ryan MW. Effects of buffered saline solution on nasal mucociliary clearance and nasal airway patency. Otolaryngol Head Neck Surg 2004;131:679 – 82. 7. Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131(6 Suppl):S1–S62. 8. Piccirillo JF, Merritt MG, Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg 2002;126:41–7. 9. Boatsman JE, Calhoun KH, Ryan MW. Relationship between rhinosinusitis symptoms and mucociliary clearance time. Otolaryngol Head Neck Surg 2006;134(3):491–3.

821

10. Baraniuk JN, Ali M, Naranch K. Hypertonic saline nasal provocation and acoustic rhinometry. Clin Exp All 2002;32:543–50. 11. Ali M, Yuta A, Baraniuk J. Effect of oxymetazoline on hypertonic saline-induced neurogenic inflammation in the human nose [abstract]. Am J Respir Crit Care Med 1998;157:A720. 12. Fang S-Y, Ali M, Yuta A, et al. Hypertonic saline nasal povocation induces substance P release: airway neurogenic inflammation redefined [abstract]. Am J Respir Crit Care Med 1998;157:A487. 13. Baraniuk JN, Ali M, Yuta A, et al. Hypertonic saline nasal provocation stimulates nociceptive nerves, substance P release, and glandular mucous exocytosis in normal humans. Am J Resp Crit Care Med 1999; 160:655– 62. 14. Mohammadian P, Schaefer D, Hummel T, et al. Experimentally induced nasal irritation. Rhinology 1999;37:175– 8. 15. Baraniuk JN, Ali M, Brody D, et al. Glucocorticoids induce ␤2adrenergic receptors in human nasal mucosa. Am J Respir Crit Care Med 1997;155:704 –10. 16. Druce HM, Bonner RF, Patow C, et al. Response of nasal blood flow to neurohormones as measured by laser-Doppler velocimetry. J Appl Physiol Respir Environ Exercise Physiol 1984;57:1276 – 83. 17. Littlejohn MC, Stiernberg CM, Hokanson JA, et al. The relationship between the nasal cycle and mucociliary clearance. Laryngoscope 1992;102:117–20. 18. Doyle WJ, Cauwenberge PB. Relationship between nasal patency and clearance. Rhinology 1987;25:167– 80.