effects of guaifenesin on nasal mucociliary clearance · pdf fileeffects of guaifenesin on...

DOI 10.1378/chest.107.3.747 1995;107;747-751 Chest

Joseph H. Sisson, Anthony J. Yonkers and Robert H. Waldman

Frequency in Healthy VolunteersMucociliary Clearance and Ciliary Beat Effects of Guaifenesin on Nasal

http://chestjournal.org/cgi/content/abstract/107/3/747Wide Web at: information and services can be found online on the World The online version of this article, along with updated

0012-3692. ). ISSN:http://www.chestjournal.org/misc/reprints.shtml(

the prior written permission of the copyright holder of this article or PDF may be reproduced or distributed without Dundee Road, Northbrook IL 60062. All rights reserved. No part2007 by the American College of Chest Physicians, 3300

CopyrightPhysicians. It has been published monthly since 1935. CHEST is the official journal of the American College of Chest

Copyright © 1995 by American College of Chest Physicians on May 28, 2008 chestjournal.orgDownloaded from

http://chestjournal.org/cgi/content/abstract/107/3/747

http://www.chestjournal.org

Effects of Guaifenesin on NasalMucociliary Clearance and Ciliary BeatFrequency in Healthy Volunteers*Joseph H. Sisson, MD, FCCP; Anthony J. Yonkers, MD;and Robert H. Waldman, MDt

Study objective: Mucociliary clearance is an importanthost defense function of the upper respiratory tract thatrequires the coordinated beating of cilia and results inthe transport of mucus to the oropharynx. Guaifenesinis a commonly prescribed drug that is reported toimprove the clearance of respiratory secretions. We hy-pothesized that guaifenesin increases nasal mucociliaryclearance related to increases in ciliary beat frequency(CBF) and that a direct relationship exists between na-sal CBF and nasal mucociliary clearance.Design: Double-blind placebo-controlled crossoverstudy.Participants: Ten healthy volunteers with a previoushistory of sinus disease.Interventions: Subjects received guaifenesin or placeboon days 1 to 7 or days 14 to 21.Measurements and Results: In vivo saccharine transittime (STT) was measured by noting the time in minutesrequired for the subject to taste a saccharin particleplaced on the inferior turbinate of the naris. The CBFwas determined by video microscopy on ten separategroups of beating ciliated nasal mucosal cells obtainedby brushing immediately after each STT determination.We found that there was no significant change between

Mucociliary clearance is an important host de-fense function of the airways. This function

requires the coordinated beating of cilia which resultsin the transport of mucus to the oropharynx. Al-though the motor activity of cilia is certainly respon-sible in large part for the propulsion of mucus out ofthe airway, the linkage between ciliary motility andmucociliary clearance is poorly understood with nodirect relationship described between the frequencyof beating cilia and mucus clearance rates in man.The clinical impact of a dysfunctional mucociliaryclearance mechanism is clear, however, since indi-viduals with genetically defective mucociliary clear-ance mechanisms are plagued with cough and re-current upper respiratory tract infections.1

*From the Department of Medicine (Drs. Sisson and Waldman)and the Department of Otolaryngology (Dr. Yonkers), Univer-sity of Nebraska Medical Center, Omaha.

t Deceased.Manuscript received March 7, 1994; revision accepted July 14.Reprint requests: Dr. Sisson, University of Nebraska MedicalCenter, 600 South 42nd Street, Omaha, NE 68198-5300

the guaifenesin- or placebo-treated groups from baselinevalues of STT (p=0.94) or CBF (p=0.46). Regressionanalysis demonstrated no relationship between STT andCBF for repeated measures within subjects (meanr2=0.18; mean p=0.66) and between STT and CBF whenall paired measurements were combined across subjects(r2=0.47; p=0.46).Conclusion: We conclude that guaifenesin exerts nomeasurable effect on in vivo nasal mucociliary clear-ance or ex vivo nasal ciliary motility in healthy volun-teers with previous sinus disease. In addition, there ap-pears to be no relationship between nasal STT measuredin vivo and CBF measured ex vivo. The lack of correla-tion is most likely due to variations in CBF related tosampling artifacts introduced by the nasal brushingprocess. (Chest 1995; 107:747-51)

CBF=ciliary beat frequency; STT=saccharin transit time

Key words: ciliary motility; guaifenesin; mucociliaryclearance; nasal mucus clearance

Guaifenesin is a compound reported to enhanceairway mucus clearance and is commonly prescribedto patients with productive cough, nasal congestion,or excessive mucus production. While one recentstudy suggests that guaifenesin may improve nasalsymptoms associated with impaired clearance,2 fewhave shown any clear effect of guaifenesin on directmeasures of mucociliary clearance,3 and none haveexamined the drug's impact on nasal ciliary motilityor mucus clearance in the nose.The current study examines two hypotheses: (1)

Does guaifenesin increase nasal mucociliary clear-ance in vivo, as assessed by the saccharin transit time(STT), or nasal ciliary beat frequency (CBF), as as-sessed by nasal brushing and ex vivo microscopy, orboth? (2) Does a relationship exist between nasal CBFand nasal STT? We report the effect of guaifenesinon both in vivo STT and ex vivo CBF determined inthe same individuals repeatedly over time and alsoexamine the relationship between these two measuresof nasal mucociliary function within and acrossindividuals.

CHEST /107 / 3 / MARCH, 1995 747



Guaifenesin Placebo ort--- or Placebo _ 4 Washout-NofIso Guaifenesin --

Day# 0 4 7 14 18 21STT & CBF t t t t t t

FIGURE 1 Representation of in vivo nasal STT and ex vivo CBFdeterminations for each subject carried out six times throughoutthe study.

METHODSClinical Data

Subject Recruitment: The study protocol was approved by theInstitutional Review Board at the University of Nebraska Medi-cal Center prior to subject accrual. Ten healthy volunteers witha history of previous sinus problems were recruited through anadvertisement to participate in the study. All subjects had no ac-tive sinus infection, nasal or sinus discharge, fevers, nasal stuffi-ness, or other active symptoms at the time of the study. Originally12 subjects started the study, but one subject was not able tocomplete the study for personal reasons and another subjectdropped out due to an exacerbation of asthma requiring oral ste-roid therapy. The remaining ten subjects were able to completethe entire study. Informed consent was obtained for all individ-uals at the time of enrollment.

Study Design: The study was a double-blind, placebo-con-trolled crossover study in which subjects were given guaifenesin,400 mg orally, 5 times a day (2,000 mg/d) for 7 days either in thefirst or third week of the study and were given placebo during theopposite week. Guaifenesin and placebo were coded and dis-pensed by the pharmacy such that the subjects and investigatorswere blind to the code until the study was completed. The mid-dle week (day 8 through 14) was a washout period when thesubjects received no drugs. In vivo nasal STT and ex vivo CBF wasdetermined on each subject 6 times throughout the study as in-dicated in Figure 1.

Both tests were performed at the same time on each test day.In each case, the nasal STT was completed immediately prior tothe nasal brushings. Out of 60 possible paired STT and CBFmeasurements, 48 were successfully completed. Difficulty insaccharin particle placement precluded STT determination infive instances, and inadequate nasal tissue obtained by brushingprecluded CBF determination in eight instances. Eight of the tensubjects successfully completed paired measurements of STT andCBF, allowing analysis of both pre- and post-drug values of bothparameters for the guaifenesin and placebo treatment periods.

Nasal Saccharin Transit Time: The nasal STT was measuredusing a standard protocol as described.4 Briefly, the more patentnaris was subjectively determined by the subject prior to thestudy, and the saccharin was placed in this naris for all subsequentdeterminations throughout the study. A 5-mg particle of saccha-rin measuring approximately 0.5 mm in diameter was placed onthe inferior turbinate of the appropriate naris under direct visu-alization using a headlamp and a nasal speculum. After correctparticle placement was visually confirmed, a stopwatch wasstarted and the total time was recorded from initial particleplacement until the subject was able to clearly taste sweetness. Ifthe subject was unable to taste any sweetness after 30 min, anadditional particle of saccharin was placed on the anterior aspectof the subject's tongue to exclude taste loss. In all determinations,the subjects had intact taste.Ex Vivo Ciliary Beat Frequency: Immediately following com-

pletion of the STT determination, the right and left nares werebrushed vigorously with a 2-mm diameter nylon cytology brushfor approximately 5 s in each naris on the inferior turbinate.5 Thebrush immediately was rinsed in medium 199 and the cells weremaintained at a constant temperature of 370C while being

transported to the laboratory. The cells were resuspended uponarrival at the laboratory; they were placed on a glass slide witha coverslip and examined by phase-contrast microscopy. Thetemperature of the microscope stage was maintained electroni-cally at 370C with a heated stage throughout the experiment. Thesample was examined for ten separate groups of beating ciliatedcells, and CBF was determined by recording the fields on video-tape and performing frame-by-frame slow-motion video analysisas described.6

Statistical Analysis

All pre- and post-drug comparisons were made using the pairedStudent's t test. The relationships between STT and CBF weredetermined using a linear regression statistic.

RESU7LTS

Effect of Guaifenesin and Placebo on SaccharinTransit TimeThe effect of guaifenesin was examined by STT.

The baseline STT for individuals prior to guaifene-sin and following 7 days on 2,000 mg/d was not sig-nificantly different (pre, 14.9 ± 1.2 min vs post,14.1± 1.7 min; p=0.31; Fig 2, A). Similarly, therewas no significant difference between the STT mea-sured before and at the end of the placebo period of7 days (pre, 16.8+2.1 min vs post, 15.5+1.2 min;p=0.28; Fig 2, B). When the change over seven daysof treatment for guaifenesin was compared with thechange with placebo relative to the baseline STT,there also was no significant difference betweenguaifenesin and placebo (guaifenesin, -0.8 ± 1.4 minvs placebo, -1.3±1.6 min; p=0.46; Fig 2, C).

Effect of Guaifenesin and Placebo on CiliaryBeat FrequencyThe effect of guaifenesin on CBF also was exam-

ined. The mean CBF from each individual prior toguaifenesin (day 0 or 14) was compared with themean CBF at the end of the 7 days of guaifenesintreatment (day 7 or 21). There was no significantchange in CBF pre- to post-drug (pre, 9.4 ± 0.4 Hz vspost, 9.2±0.4 Hz; p=0.39; Fig 3, A). This was sim-ilar to the results obtained for placebo in which CBFalso did not change significantly (pre, 9.8 ± 1.1 Hz vspost, 9.9 ±0.5 Hz; p=0.87; Fig 3, B). The change inCBF after 7 days on the drug compared with base-line also was not significantly different (guaifenesin,-0.3 ± 0.4 Hz vs placebo, 0.1 + 0.9 Hz; p=0.46; Fig3, C).

Relationship Between Saccharin Transit Timeand Ciliary Beat Frequency Within and AcrossSubjectsThe relationship between CBF and STT was

examined within each subject on repeated days usingregression analysis. In all but one subject there was norelationship between STT and CBF (average r2=0. 18;average p=0.66; data not shown). The only exception

Effect of Guaifenesin on Mucociliary Clearance and Cilia Beat Frequency (Sisson, Yonkers, Waldman)748



B30-

25-

a) 20-

.E -

15

10-

Placebo

+ I

p = 0.28

Pre Placebo Post Placebo

Placebo

0r00

FIGU>RE 2. Effect of guaifenesin vs placebo on nasal STT. Panels A and B, The vertical axes representthe nasal STT expressed in minutes and the horizontal axes represent the pre-drug (day 0 or 14) andpost-drug (day 7 or 21) STT determinations with paired samples for each subject connected by lines.Panel A demonstrates the values for all subjects receiving guaifenesin and panel B shows those for allsubjects receiving placebo. The mean + 1 SEM for the group of subjects is displayed next to the indi-vidual data points for each group. Panel C, The vertical axis represents the change in STT comparedwith pre-drug values and the horizontal axis represents the guaifenesin and placebo treatment groups.

The p values were determined using the Student's paired t test.

in which a positive correlation was seen between thetwo variables was in one subject (r2=0.84; p=0.01;data not shown). We also examined the relationshipbetween CBF and STT across all subjects combiningall data points. There was no significant relationshipbetween these two variables in 10 subjects for 47 in-dependent paired measurements (r2=0.04; p=0.18;Fig 4). This lack of correlation existed regardless ofhow the data were examined with regard to mea-

surements made while the subject was taking placeboor guaifenesin or was not receiving any drugs.

DISCUSSION

Our study examined the effect of guaifenesin on

mucociliary clearance as measured in vivo by nasalSTT and on ciliary motility as measured ex vivo byCBF. We found that guaifenesin had no significanteffect on either of these measures of nasal mucocil-iary function. Our observation bolsters the experi-ence in the literature in which few well designedstudies have shown that guaifenesin promotes mu-

cociliary clearance. Thomson and coworkers3 foundthat guaifenesin had a small but positive effect on

lung clearance of inhaled radiolabeled particles frombronchitic but not normal subjects. Unfortunately, allbut one of the normal subjects in that study smoked

heavily, and the authors only examined the effect ofa single 600-mg dose of guaifenesin. That study alsodiffered from ours in that the authors examined lungclearance, while we examined nasal clearance.Wawrose and colleagues2 found that guaifenesin wasassociated with symptomatic improvement in nasalcongestion and a subjective decrease in nasal secre-

tion thickness when given to a group of HIV-positivepatients with sinonasal symptoms. They did not ex-

amine any objective measure of mucociliary func-tion, however, and their study, while double-blinded,was not a crossover design.2 For these reasons, our

study is important because we examined the effectsof guaifeenesin in a healthy population, we examinedobjective measurements of nasal mucociliary func-tion, and we used a double-blind crossover design tominimize investigator and subject bias.

There are several possible explanations why we

could not measure an effect of guaifenesin on STT or

CBF: (1) Guaifenesin may be ineffective in promot-ing nasal mucociliary clearance. (2) Guaifenesin maynot penetrate the nasal mucosa. (3) Nasal STT onlyassesses clearance of the nares and may have no re-

lationship to clearance of the lower respiratory tract.(4) Nasal STT may be insensitive to small drug effectssuch that the test may not be capable of detecting a

CHEST / 107 / 3 / MARCH, 1995 749

A30- Guaifenesin

25-

(j 20-C:

.Et 15-

10-

I +

Pre Drug Post Drug

C Guaifenesin10-8-

,, 6-o01 4-C: 2--2-

Cl) -4< -6-

-8--10-

0 00B

p =0.46

;) v ffl



GuaifenesinB

15-

14-

13-

12-

,.11-NZ

, 10-

8-

7-

6-

I

p = 0.39

Pre Drug Post Drug

C5-

4-3-

p- 2-

I 1-LL 0-m d-1-< -2-

-3--4--5-

Guaifenesin

Ie@el

0

p =0.46

Placebo

D - I

Pre Placebo Post Placebo

Placebo

II

I

FIGURE 3. Effects of guaifenesin vs placebo on CBF. Panels A and B, The vertical axes represent CBFexpressed in cycles per second (Hertz) and the horizontal axes represent the pre-drug (day 0 or 14) andpost-drug (day 7 or 21) CBF determinations with paired samples for each subject connected by lines.Panel A demonstrates the values for all subjects receiving guaifenesin and panel B shows those for allsubjects receiving placebo. Each data point represents the mean of ten separate CBF measurementsmade from different groups of ciliated cells obtained from a single nasal sample. The mean + 1 SEMfor the group of subjects is displayed next to the individual data points for each group. Panel C, Thevertical axis represents the change in CBF compared with the pre-drug values, and the horizontal axisrepresents the guaifenesin and placebo treatments groups. The probability values were determinedusing the Student's paired t test.

small change in clearance. There also are severalreasons why guaifenesin may not alter ciliary motil-ity measured by ex vivo CBF including one thatchanges in in vivo CBF may have occurred; however,the ex vivo method used to determine CBF in thisstudy introduces enough preparation artifact that thischange cannot be detected. Mucus transit ratesprobably depend not just on CBF, but also on changesin the height and character of the periciliary fluidpresent on the surface of the ciliated epithelium. Ourstudy did not examine changes in nasal mucus

viscosity, which guaifenesin might have affected.Such an effect could impact on effective clearancewithout altering CBF or STT. Another limitation ofour study is that it only examined healthy volunteerswith no active nasal or sinus disease. It could well bethat the drug is active in a sicker patient population,which has been suggested with regard to guaifenes-in's effect on secretions in chronic bronchitic sub-jects,3 but has no significant impact on well individ-uals. Lastly, our study only examined nasal effects onmucociliary function, which does not exclude possi-ble effects that may have been beneficial in thesinuses or other parts of the respiratory tract.Our second hypothesis proposed that there is a di-

rect relationship between nasal mucociliary clear-

ance in vivo, as assessed by STT, and nasal ciliarymotility, measured ex vivo as CBF. We found no re-

lationship between these measures of mucociliaryfunction. One might predict that if a relationshipexisted, it would be an inverse one in which fasterCBF would result in shorter STT. We did not observethis relationship, however. The only statistically sig-nificant relationship between STT and CBF we ob-served was present in only one subject, and this rela-tionship was the opposite of what our hypothesissuggested. There are several reasons why we may nothave seen any relationship between these two vari-ables: (1) They may be valid but independent mea-

sures of mucociliary function. (2) There is likely to bean important artifact introduced into the CBF de-terminations because these are measured ex vivorather than in vivo. (3) Factors such as humidity, lo-cal inflammation, and the presence of irritants mayinfluence clearance or ciliary motility, or both, on a

given day. We suspect that removing nasal ciliatedcells by the brushing technique and observing themex vivo introduces significant changes in motility andrepresents the most likely explanation for the vari-ance in CBF that we observed. This is somewhatsupported by the fact that there was more variationin the ex vivo CBF measurements than there was in

Effect of Guaifenesin on Mucociliary Clearance and Cilia Beat Frequency (Sisson, Yonkers, Waldman)

A15-

14-

13-

12-

_ 11 -Nl -r

LL 10-m -

0 9-

8-

6-

0

a1

750



30-

25-

20-

15-

10-

0(D

§

0Q0

0 0 @

0 050 0

000

Q SOSO 0

0 0

0 0(2

©2©2 02

5 6 7 8 9 10 11 12 13 14 15

CBF (Hz)

FIGURE 4. Relationship of STT to CBF. The vertical axis repre-

sents the STTs expressed in minutes, and the horizontal axis rep-

resents the CBF expressed in cycles per second (Hertz). Each datapoint represents the paired simultaneous STT and CBF determi-nations for a given subject. The subject numbers are displayed as

open circles (for the group which received guaifenesin during thefirst week) and solid circles (for the group which received placeboduring the first week). There was no statistically significant rela-tionship between STT and CBF using linear regression analysis(r2=0.04; p=018).

the STT measurements when repeated measure-

ments were examined within each individual. Analternative explanation may be that there should belittle change in either of these in a well, healthy out-patient population such that not enough variation ispresent to detect a relationship between these twovariables using regression analysis. For this reason,

we also examined the relationship of both of thesevariables for the group as a whole. When the across-

subject relationship between CBF and STT was

examined, there also was no relationship betweenthese two variables (Fig 4). Again, the same expla-nations could support this lack of a linear relation-ship.

In summary, we conclude that guaifenesin has nosignificant impact on either nasal STT or ex vivo CBFin healthy volunteers with a previous history of sinusdisease. Nasal STT and ex vivo CBF appear to be in-dependent measures of mucociliary function, whichare most likely to be related to sampling artifacts in-troduced by the nasal brushing technique or the exvivo nature of the CBF assay.ACKNOWLEDGMENTS: The authors thank Proctor and Gam-ble for their sponsorship of this study. We also wish to acknowl-edge Kathryn May for her valuable technical assistance inperforming the nasal brushings and CBF measurements and thenursing stalf of the Otolaryngology Clinic for assisting in subjectaccrual and the nasal STT determinations.

REFERENCES1 Afzelius B. The immotile cilia syndrome and other ciliary dis-

eases. Int Rev Exp Pathol Acta Cytologica 1979; 19:1-432 Wawrose SF, Tami TA, Amoils CP. The role of guaifenesin in

the treatment of sinonasal disease in patients infected with thehuman immunodeficiency virus (HIV). Laryngoscope 1992;102:1225-28

3 Thomson ML, Pavia D, McNicol MW. A preliminary study ofthe effect of guaifenesin on mucociliary clearance from thehuman lung. Thorax 1973; 28:742-47

4 Andersen I, Lundqvist G. Nasal mucociliary function inhumans. In: Lenfant C, ed. Lung biology in health and disease.New York: Dekker, 1977; 427-52

5 Rutland J, Griffin W, Cole P. Nasal brushing and measurementof ciliary beat frequency: an in vitro method for evaluatingpharmacologic effects on human cila. Chest 1981; 80:865-67

6 Wanner A, Maurer D, Abraham W, et al. Effects of chemicalmediators of anaphylaxis on ciliary function. J Allergy ClinImmunol 1983; 72:663-67

CHEST / 107 / 3 / MARCH, 1995 751

ina)

t)

Z:)



DOI 10.1378/chest.107.3.747 1995;107;747-751 Chest

Joseph H. Sisson, Anthony J. Yonkers and Robert H. Waldman Beat Frequency in Healthy Volunteers

Effects of Guaifenesin on Nasal Mucociliary Clearance and Ciliary

This information is current as of May 28, 2008

& ServicesUpdated Information

http://chestjournal.orghigh-resolution figures, can be found at: Updated information and services, including

Permissions & Licensing

http://chestjournal.org/misc/reprints.shtmlonline at: (figures, tables) or in its entirety can be found Information about reproducing this article in parts

Reprints

http://chestjournal.org/misc/reprints.shtmlonline: Information about ordering reprints can be found

Email alerting service

of the online article. this article sign up in the box at the top right corner Receive free email alerts when new articles cite

Images in PowerPoint format

directions. slide format. See any online article figure fordownloaded for teaching purposes in PowerPoint Figures that appear in CHEST articles can be


http://chestjournal.org

http://chestjournal.org/misc/reprints.shtml

http://chestjournal.org/misc/reprints.shtml


effects of guaifenesin on nasal mucociliary clearance · pdf fileeffects of guaifenesin on...

Documents