The Laryngoscope
`Lippincott-Raven Publishers, Philadelphia
`0 1997 The American Laryngological,
`Rhinological and Otological Society, Inc.
`
`Mucociliary Clearance and Buffered
`Hypertonic Saline Solution
`
`Andrew R. Talbot, MD; Timothy M. Herr, MD; David S. Parsons, MD
`
`Nasal irrigations have been used for centuries
`without any scientific data to determine efficacy.
`For 10 years, the senior author has used buffered
`hypertonic saline nasal irrigation for patients with
`acute/chronic sinusitis and for those having under-
`gone sinus surgery. A simple study was undertaken
`using volunteers without any significant sinonasal
`disease. Patients served as their own control using
`a saccharin clearance test before any nasal irriga-
`tion was used. Patients then used one of two solu-
`tions to irrigate their nose-buffered normal saline
`or buffered hypertonic saline-and were then
`retested. On a separate day, the control test was re-
`peated, followed by irrigation with the alternate so-
`lution and a second saccharin clearance test. The
`outcome showed buffered hypertonic saline nasal
`irrigation to improve mucociliary transit times of
`saccharin, while buffered normal saline had no
`such effect.
`
`Laryngoscope, 107:500-503,1997
`
`INTRODUCTION
`For more than a century, physicians have advo-
`cated nasal irrigation for patients with sinonasal
`disease. Several different solutions have been sug-
`gested to patients without any documented evidence
`of significant change in symptomatology. For more
`than 10 years, the senior author (D.s.P.) has used a
`solution that can be made very inexpensively by pa-
`tients at home1 (Table I). The results, as determined
`by favorable patient responses, seemed promising,
`but statistical outcomes were lacking.
`Both surgical and nonsurgical patients with a
`history of chronic sinusitis have been encouraged to
`
`From the ENT Department, Sydney Hospital (A.R.T.), Sydney, Aus-
`tralia; and the Division of Otolaryngology (T.H., D.s.P.), University of Mis-
`souri School of Medicine, Columbia, Missouri.
`Editor’s Note: This Manuscript was accepted for publication October
`14, 1996.
`Send Reprint Requests to David S. Parsons, MD, University of Mis-
`souri School of Medicine, One Hospital Dr., MA314, Columbia, MO 65212,
`U.S.A.
`
`Laryngoscope 107: April 1997
`500
`
`use buffered hypertonic saline nasal irrigation.
`Nasal irrigation aids in the clearance of secretions,
`debris, and intranasal crusts. This is also important
`in the postoperative period to reduce the risk of ad-
`hesions and to promote ostiomeatal patency.
`For many decades, physicians have often pre-
`scribed the use of “physiologic” or “normal” saline
`(0.9%), sometimes buffered to a mildly alkaline so-
`lution. A hypertonic solution, however, may actually
`reduce edema through diffusion of osmolar gradi-
`ents. This should enhance mucociliary clearance and
`improve patency of sinus ostia. In vitro studies from
`Meyers et a1.2 have shown a 12-fold increase in mu-
`cociliary clearance (MCC) using animal tracheal
`mucosa which was irrigated with a similar buffered
`hypertonic solution.
`The aim of this study was to determine if MCC
`in vivo was improved significantly by the use of a
`buffered hypertonic saline (3%, pH 7.6) vs. buffered
`normal saline irrigations.
`MATERIALS AND METHODS
`Twenty-one volunteers aged 25 to 45 years were se-
`lected to participate in the study. None of the 21 had any
`history of upper respiratory tract infection symptoms
`within the 3 weeks prior to the study. In addition, there
`could be no history of significant allergies, smoking, or re-
`current exposure to smoke-filled environments. Patients
`taking systemic or topical sympathomimetics, parasympa-
`thomimetic agents, or antihistamines were excluded, as
`were those who had undergone sinus surgery in the past.
`No volunteer had engaged in any strenuous exercise
`within 30 minutes prior to testing.
`Mucociliary clearance was assessed by using the sac-
`charin clearance test method.3.4 Testing was performed in
`an area of constant humidity with a room temperature of
`68 to 72°F (20” to 22°C). The subject was asked to sit head
`upright and several saccharin grains were placed on the
`medial aspect of the inferior turbinate 1 to 1.5 cm behind
`its anterior border using a moistened cotton swab. After
`placement of the saccharin grains, the subject was to re-
`frain from sniffing, bending, or sneezing. The individual
`was then instructed to swallow at 30-second intervals and
`
`Talbot et al.: Mucociliary Clearance
`
`1
`
`CIP2136
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`TABLE I.
`Directions for Preparation and Use of the Solution.
`Preparation
`1. Clean a 1 -quart glass jar carefully, then fill it with bottled water.
`You need not boil the water.
`2. Add 2 to 3 heaping teaspoons of pickling or canning salt. DO
`NOT use table salt, because it contains additives.
`3. Add 1 rounded teaspoon of baking soda (pure bicarbonate).
`4. Store at room temperature and shake or stir before each use.
`5. Mix a new batch weekly.
`Use
`1. Pour some of the mixture into a clean bowl. Warming it to body
`temperature may help, but make sure it is NOT HOT.
`2. Fill the syringe or bulb irrigator. To avoid contamination, DO
`NOT place bulb or syringe into jar.
`3. Stand over the sink or in shower and squirt the mixture into
`each side of the nose several times.
`4. Rinse the nose two to three times daily.
`
`to record the time of the saccharin taste to the nearest
`half minute.
`Each volunteer was initially assessed for a control
`saccharin transit time. Subjects were then given 10 sprays
`with a handheld atomizer of either a 0.9% saline solution
`or a 3% saline solution (both buffered to pH 7.6) to one
`side of the nose. Ten additional sprays were then given to
`the same side after an interval of 1 minute. A second sac-
`charin transit time was performed 10 to 20 minutes after
`irrigation to assess any change. This same procedure was
`then repeated on a different day with the opposite con-
`centration used on the initial trial. Again, a control time
`was obtained prior to testing with the alternate saline so-
`lution, followed by a second transit time.
`To allow dispersal of excess irrigation fluid and time
`for an optimal ciliary response to the altered physiologic
`environment, a period of 10 to 20 minutes separated the
`nasal irrigation and the placement of the saccharin. Each
`subject acted as hisher own control for the purposes of
`analysis. For each subject, transit times following irriga-
`tion are compared only with the subject’s own control time
`for that day to compensate for physiological variances
`such as the nasal cycle or other daily variations in nasal
`physiology.*
`The Wilcoxon’s signed rank .test was used to analyze
`the data to determine any differences in changes in times,
`both in minutes and percent of baseline.
`RESULTS
`Results are shown as saccharin transit times in
`Tables I1 and 111. This compares times both before
`and after buffered hypertonic saline nasal irrigation
`as compared to buffered normal saline nasal irriga-
`tion. There was no significant difference in control
`values between the solutions (P = 0.271, thus ruling
`out any bias due to differing baseline times prior to
`testing with the buffered hypertonic or normal saline
`solutions. Transit time decreased from baseline in the
`buffered hypertonic trials by 17% (P = 0.007) com-
`
`Laryngoscope 107: April 1997
`
`TABLE II.
`Results After Treatment With Hypertonic Saline.
`
`Control
`(min)
`5.5
`7.5
`9.0
`10.0
`8.0
`18.0
`28.0
`17.0
`15.0
`11.5
`23.0
`6.5
`12.0
`14.0
`15.0
`8.0
`16.5
`14.0
`8.0
`6.0
`30.5
`13.5
`
`After BHTS
`(min)
`5.5
`6.5
`6.0
`6.5
`6.5
`8.5
`15.5
`13.0
`12.5
`9.5
`9.0
`7.0
`8.5
`11.0
`10.0
`10.0
`11.0
`17.0
`10.5
`6.0
`28.0
`10.5
`
`Change
`(min)
`0
`-1 .o
`-3.0
`-3.5
`-1.5
`-9.5
`-12.5
`-4.0
`-2.5
`-2.0
`-14.0
`+.5
`-3.5
`-3.0
`-5.0
`+2.0
`-5.5
`+3.0
`+2.5
`0
`-2.5
`-3.0
`
`Change
`(“4
`0
`-1 3
`-33
`-35
`-1 9
`-53
`-45
`-24
`-1 7
`-1 7
`-6 1
`+8
`-29
`-21
`-33
`-25
`-33
`+21
`+31
`0
`-8
`-1 7
`
`Subject
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`Mean:
`
`BHTS = buffered hypertonic saline treatment.
`
`pared with a 2% decrease (P = 0.71) for buffered nor-
`mal saline. The difference between the percent
`changes was statistically significant, with a P value
`of 0.013.
`The changes in minutes were also significant.
`The hypertonic saline produced a mean improve-
`ment of 3.1 minutes (SD = 4.4; P = 0.002) vs. 0.14
`minutes in the buffered normal saline group (SD =
`7.0; P = 0.69). Again, the difference of changes was
`statistically significant to a P value of 0.02. This
`shows a marked improvement of saccharin transit
`time with use of buffered hypertonic saline irriga-
`tions as compared to buffered normal saline, both in
`percent change and in change in minutes. Because
`of intersubject baseline variability, the clinical im-
`portance of time changes in minutes is questionable.
`
`DISCUSSION
`Otolaryngologists and rhinologists commonly
`recommend nasal irrigations in the treatment of pa-
`tients with acute and chronic sinusitis. Nasal irri-
`gations have also been utilized in the postoperative
`care of functional endoscopic sinus (FES) surgical
`patients. The irrigations help to clear static secre-
`tions, rinse infective debris, and minimize crusting,
`which may obstruct normal sinonasal drainage or
`lead to adhesions. The senior author uses a 3%
`
`Talbot et al.: Mucociliary Clearance
`50 1
`
`2
`
`

`

`TABLE Ill.
`Results After Treatment Wtih Normal Saline.
`
`Subject
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`Mean:
`
`Control
`(rnin)
`13.0
`12.0
`10.0
`11.5
`11.5
`13.5
`45.0
`17.0
`18.5
`15.0
`29.0
`7.0
`7.0
`9.0
`9.5
`14.0
`13.5
`23.0
`9.0
`8.0
`14.0
`15.0
`
`After NS
`(rnin)
`13.5
`10.0
`11.5
`11.5
`13.5
`13.5
`20.0
`23.0
`15.0
`15.0
`43.0
`6.5
`6.0
`7.5
`11.0
`8.0
`13.0
`28.0
`14.0
`6.5
`17.0
`14.5
`
`Change
`(min)
`+.5
`-2.0
`+1.5
`0
`+2.0
`0
`-25.0
`+6.0
`-3.5
`0
`+14.0
`-.5
`-1 .o
`-1.5
`+1.5
`-6.0
`-.5
`+5.0
`+5.0
`-1.5
`+3.0
`-.14
`
`Change
`(%)
`+4
`-1 7
`+15
`0
`+17
`0
`-56
`+35
`-1 9
`0
`+48
`-7
`-1 4
`-1 7
`+16
`-43
`-4
`+22
`+56
`-1 9
`+2 1
`-2
`
`saline irrigation formula buffered to approximately
`pH 7.6 in the treatment of patients with acute and
`chronic sinusitis and as an adjunct in the manage-
`ment of patients with significant rhinitis secondary
`to other disorders.
`It has been suggested that saccharin dissolution
`in this test method provides a less accurate assess-
`ment of MCC than tagged insoluble particles, as the
`saccharin mixes between sol and gel layers of the mu-
`cociliary blanket and is not carried solely in the su-
`perficial gel layer. This layer is usually propelled at a
`more uniform rate by the tips of the cilia, whereas
`fluid motion in the sol layer may oscillate back and
`forth.4 However, it is likely that any such limitation,
`if present in vivo, would tend to underestimate the ef-
`fect of changes in MCC and the improved clearance
`rates with the buffered hypertonic saline nasal irri-
`gations. In fact, Proctor has found close correlation,
`for each individual, between clearance rates with sac-
`charin and tagged insoluble particles.5
`The results of transit times with the buffered
`hypertonic saline from this study demonstrate de-
`creased mucous clearance times in the majority of
`subjects (15/21, 71%) (Table 11). The average im-
`provement in these times was 4.87 minutes. Two
`subjects had no change in MCC rates after 10 to 20
`minutes and four subjects actually recorded slower
`
`Laryngoscope 107: April 1997
`502
`
`times. Interestingly, the number of patients with im-
`proved transit times after the buffered 0.9% saline
`was less than might be expected (10/21,48%).
`Mucociliary clearance may be modified by
`changes in ciliary beat frequency (CBF), and rheo-
`logic changes in the mucous blanket such as viscosity
`and shearing forces. Other factors, including cilia1
`loss, outflow obstruction, and mucosal apposition,
`may also play a role, especially in chronic sinusitis.
`Rheologic alterations in this study may be the
`most important factor. Saline improves MCC in
`healthy and cystic fibrosis (CF) patients.6 A change
`with normal saline irrigations in healthy patients
`was not seen by Majima et al., but they did see a sig-
`nificant change in those with sinusitis. This may be a
`result of the saline increasing the depth and thinning
`of the sol layer of mucous.7 NaCl also decreases the
`viscosity of mucus in vitro.8 Pavia et al.9 have noted
`increased mucous clearance from the lung (no change
`in cough pattern) with the use of small volumes of
`7.1% nebulized saline; clearance rates were almost
`twice as fast as the control group for 50 minutes.
`These changes may be more pronounced in
`pathologic processes such as sinusitis. Some authors
`have cited increased nasal mucociliary times on sac-
`charin testing of sinus patients vs. normal controls.7
`Increasing viscosity, as frequently is seen in
`chronic sinusitis, is believed to gradually decrease
`CBF.10 In addition, outflow obstruction, crusting,
`mucosal apposition, and altered ventilation are all
`factors which may lead to worsening MCC. All sub-
`jects in this study had no symptoms of infective
`rhinitis or sinusitis. Saline irrigations, and espe-
`cially buffered hypertonic saline, may have resulted
`in even greater changes in symptomatic patients.
`Buffered hypertonic saline is a mildly alkaline
`solution. It is believed that an acidic milieu may
`cause mucus to be present in a “gel” or viscous state.
`Alkaline environments cause the mucus to be in a
`“sol7’ state.11 This is similar to the gel and sol phases
`of mucous mentioned previously. The thickened mu-
`cous may be more effective in isolating particulate
`matter, however, it may lead to an increase in the
`amount of tether between the gel and sol layers12 and
`thus interfere with normal mucociliary function.
`Other factors in vivo may also be related to
`nasal MCC. This study did not objectively address
`the effect of buffered hypertonic saline on nasal pa-
`tency. It has been frequently noted that there is at
`least a subjective improvement in nasal patency in
`patients with congestive rhinitis. The exact role of
`nasal patency in MCC will require further study.
`
`CONCLUSION
`Buffered hypertonic saline nasal irrigation is an
`important addition to the care of sinus disease, both
`
`Talbot et al.: Mucociliary Clearance
`
`3
`
`

`

`chronic and postsurgical. Improvement in mucocil-
`iary transit times was seen with buffered hypertonic
`saline solutions vs. buffered normal saline (3.1
`minute improvement compared to 0.14 minutes,
`P = 0.02, and 17% improvement compared to 2%,
`P = 0.013). Buffered hypertonic saline irrigations
`should be used in chronic and postoperative sinus
`patients. Those with other causes of rhinitis, includ-
`ing acute sinusitis, may also benefit from regular
`nasal irrigation with this solution.
`
`BIBLIOGRAPHY
`1. Parsons DS. Chronic sinusitis: a medical or surgical disease?
`Otolaryngol Clin North Am 1996;29:1-10.
`2. Meyers, R. Personal communication, 1994.
`3. Stanley P, MacWilliam L, Greenstone M, et al. Efficacy of a
`saccharin test for screening to detect abnormal mucocil-
`iary clearance. Br J Dis Chest 1984;78:62-5.
`4. Littlejohn MC, Stiernberg CM, Hokanson JA, et al. The rela-
`tionship between the nasal cycle and mucociliary clear-
`ance. Laryngoscope 1992;102:117-20.
`5. Proctor DF. The mucociliary system. In: Proctor DF, Andersen
`I, eds. The Nose: Upper Airway Physiology and the Atmos-
`
`pheric Environment. New York: Elsevier Biomedical Press
`1982: 245.
`6. Middleton PG, Geddes DM, Alton EW. Effect of amiloride and
`saline on nasal mucociliary clearance and potential differ-
`ence in cystic fibrosis and normal subjects. Thorax 1993;
`48:812-6.
`7. Majima Y, Sakakura Y, Matsubara T, et al. Mucociliary clear-
`ance in chronic sinusitis: related human nasal clearance and
`in vitro bullfrog palate clearance. Biorheology 1983; 20:
`251-62.
`8. Palmer KNV Reduction of sputum viscosity by a water aerosol
`in chronic bronchitis. Lancet 1960;1:91.
`9. Pavia D, Thomson ML, Clarke SW. Enhance clearance of secre-
`tions from the human lung after the administration of hy-
`pertonic saline aerosol. Am Reu Rspir Dis 1978;117:
`199-203.
`10. Luk CKA, Dulfano MJ. Effect of pH, viscosity and ionic-
`strength changes on ciliary beating frequency of human
`bronchial explants. Clin Sci 1983;64:449-51.
`11. Breuninger H. Dir Rolle der Tonizitat und Viskositat von Lo-
`sungen in der Aktivitat des Flimmerepithels der Nasen-
`schleimhaut. Arch Ohr Nus Kehlkopfheilk 1964;184:
`133-8.
`12. Holma B, Lindegren M, Andersen JM. pH Effects on ciliomotil-
`ity and morphology of respiratory mucosa. Arch Enuiron
`Health 1977;32:21&25.
`
`Laryngoscope 107: April 1997
`
`Talbot et al.: Mucociliary Clearance
`503
`
`4
`
`