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Particularities and Clinical Applicability of Saccharin Transit Time Test

Abstract

Introduction

The importance ofmucociliary clearance (MCC) for the respiratory system homeostasis is clear. Therefore, evaluating this defense mechanism is fundamental in scientific research and in the clinical practice of pulmonology and of associated areas. However, MCC evaluation has not been so usual due to the complexity ofmethods that use radiolabeled particles. Nevertheless, as an interesting alternative, there is the saccharin transit time (STT) test. This method is reproducible, simple to perform, noninvasive, does notdemand high costs, and has been widely used in studies of nasalMCC. Although the STT test is widely used, there is still lack of a detailed description of its realization.

Objective

The present literature review aims to provide basic information related to the STT test andto present the findings of the previous studies that usedthismethod, discussing variations in its execution, possible influences on the obtained results and limitations of the method, as well as to relate our experience with the use of STT in researches.

Data Synthesis

There are several factors that can alter the results obtained from STT tests, which would raise difficulties with proper interpretation and with the discussion of the results among different studies.

Conclusions

Saccharin transit time is awidely usedmethod for the evaluation of nasal MCC, and therefore, the standardization related to the previous and concurrent to test orientations, and also its execution, become essential to improve its accuracy, and allow comparisons among different studies.

Keywords:
mucociliary clearance; airway management; mucus

Introduction

Mucociliary clearance (MCC) is an important respiratory system defense mechanism, since the human airway surfaces are constantly exposed to various particles and microorganisms present in the ambient air.11 Scheuch G, Kohlhäufl M, MöllerW, et al. Particle clearance from the airways of subjects with bronchial hyperresponsiveness and with chronic obstructive pulmonary disease. Exp Lung Res 2008; 34(09):531-549 22 Nakagawa NK, FranchiniML, Driusso P, de Oliveira LR, Saldiva PH, Lorenzi-Filho G. Mucociliary clearance is impaired in acutely ill patients. Chest 2005;128(04):2772-2777 33 Moriarty BG, Robson AM, Smallman LA, Drake-Lee AB. Nasal mucociliary function: comparison of saccharin clearance with ciliary beat frequency. Rhinology 1991;29(03):173-179 44 Hasani A, Toms N, Agnew JE, Lloyd J, Dilworth JP. Mucociliary clearance in COPD can be increased by both a D2/beta2 and a standard beta2 agonists. Respir Med 2005;99(02):145-151 Its effectiveness depends on the quantity and on the quality of the mucus, on the structure, the synchrony and frequency of ciliary beating, and on the interaction between these components.55 Ferri RG, Zonato A, Guilherme A, et al. Análise do clearance mucociliar nasal e dos efeitos adversos do uso de CPAP. Rev Bras Otorrinolaringol 2004;70(02):150-155 66 Elliott MK, Sisson JH, Wyatt TA. Effects of cigarette smoke and alcohol on ciliated tracheal epithelium and inflammatory cell recruitment. Am J Respir Cell Mol Biol 2007;36(04):452-459 77 Smith DJ, Gaffney EA, Blake JR. Modelling mucociliary clearance. Respir Physiol Neurobiol 2008;163(1-3):178-188

Mucus is a barrier that entraps inhaled microorganisms in its mobile layer, and the cilia are the propellants, which act through coordinated beating. The interaction of these components is responsible for the removal of microorganisms from the upper and lower airways toward the oropharynx, where they are swallowed or expectorated, which avoids them from entering into direct contact with epithelial cells or reaching the alveoli.88 Bhowmik A, Chahal K, Austin G, Chakravorty I. Improving mucociliary clearance in chronic obstructive pulmonary disease. Respir Med 2009;103(04):496-502 99 Mall MA. Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: lessons from mouse models. J Aerosol Med Pulm Drug Deliv 2008;21(01):13-24 1010 Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur Respir J 1998;12(04):982-988 1111 Ho JC, Chan KN, Hu WH, et al. The effect of aging on nasal mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia.AmJ Respir Crit CareMed 2001;163(04):983-988 1212 Oozawa H, Kimura H, Noda T, Hamada K, Morimoto T, Majima Y. Effect of prehydration on nasal mucociliary clearance in low relative humidity. Auris Nasus Larynx 2012;39(01):48-52

Since MCC is fundamental in lung defense, several methods have been described to evaluate it: some analyze separately the mechanical condition of the cilia (video microscopy, photometric method)33 Moriarty BG, Robson AM, Smallman LA, Drake-Lee AB. Nasal mucociliary function: comparison of saccharin clearance with ciliary beat frequency. Rhinology 1991;29(03):173-179 1313 Chilvers MA, Rutman A, O'Callaghan C. Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia. J Allergy Clin Immunol 2003;112(03):518-524 or of the mucus (contact angle measurements, displacement of mucus by simulated cough and frog palate),1414 Macchione M, Guimarães ET, Saldiva PH, Lorenzi-Filho G. Methods for studying respiratory mucus and mucus clearance. Braz J Med Biol Res 1995;28(11-12):1347-1355 1515 Trindade SH, de Mello JFJ Jr, Mion OdeG, et al. Methods for studying mucociliary transport. Rev Bras Otorrinolaringol (Engl Ed) 2007;73(05):704-712 1616 Lima Afonso J, Tambascio J, Dutra de Souza HC, Jardim JR, Baddini Martinez JA, Gastaldi AC. [Transport of mucoid mucus in healthy individuals and patients with chronic obstructive pulmonary disease and bronchiectasis]. Rev Port Pneumol 2013;19(05):211-216 and others evaluate the interaction between the mucus and the cilia (clearance of inhaled radiolabeled particles, saccharin transit time [STT] test).1717 BennettWD, Laube BL, Corcoran T, et al.Multisite comparison of mucociliary and cough clearance measures using standardized methods. J Aerosol Med Pulm Drug Deliv 2013;26(03):157-164 1818 Stanley P, MacWilliamL, GreenstoneM,Mackay I, Cole P. Efficacy of a saccharin test for screening to detect abnormal mucociliary clearance. Br J Dis Chest 1984;78(01):62-65

Methods involving radiolabeled particles are used as the reference option to measure MCC.1919 Puchelle E, Aug F, Pham QT, Bertrand A. Comparison of three methods for measuring nasal mucociliary clearance in man. Acta Otolaryngol 1981;91(3-4):297-303 However, the feasibility of this methodology is limited due to equipment and cost requirements, besides presenting some risks inherent to the exposure to radiation. The STT test was compared with the radioactively tagged particles method in the study of Puchelle et al.1919 Puchelle E, Aug F, Pham QT, Bertrand A. Comparison of three methods for measuring nasal mucociliary clearance in man. Acta Otolaryngol 1981;91(3-4):297-303 The authors found a good correlation between the methods for absolute results obtained in one measurement day and for changes between two measurement days. The STT is a useful method for scientific research, widely used in nasal MCC studies, as it is a reproducible,1818 Stanley P, MacWilliamL, GreenstoneM,Mackay I, Cole P. Efficacy of a saccharin test for screening to detect abnormal mucociliary clearance. Br J Dis Chest 1984;78(01):62-65 2020 Corbo GM, Foresi A, Bonfitto P, Mugnano A, Agabiti N, Cole PJ. Measurement of nasal mucociliary clearance. Arch Dis Child 1989;64(04):546-550 2121 Plaza Valía P, Carrión Valero F, Marín Pardo J, Bautista Rentero D, González Monte C. [Saccharin test for the study of mucociliary clearance: reference values for a Spanish population]. Arch Bronconeumol 2008;44(10):540-545 simple to perform, and noninvasive technique, besides being low-cost, making it an interesting alternative to other methods that require relatively complex, invasive, and expensive equipment, and demand greater technical aptitude from the examiners.1212 Oozawa H, Kimura H, Noda T, Hamada K, Morimoto T, Majima Y. Effect of prehydration on nasal mucociliary clearance in low relative humidity. Auris Nasus Larynx 2012;39(01):48-52 2222 Proença de Oliveira-Maul J, Barbosa de Carvalho H, Goto DM, et al. Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. Chest 2013;143(04):1091-1097 2323 Proença M, Fagundes Xavier R, Ramos D, Cavalheri V, Pitta F, Cipulo Ramos EM. [Immediate and short termeffects of smoking on nasal mucociliary clearance in smokers]. Rev Port Pneumol 2011;17(04):172-176 2424 Arnaoutakis D, Collins WO. Correlation of mucociliary clearance and symptomatology before and after adenoidectomy in children. Int J Pediatr Otorhinolaryngol 2011;75(10):1318-1321 2525 Naiboglu B, Deveci I, Kalaycik C, et al. Effect of nasolacrimal duct obstruction on nasal mucociliary transport. J Laryngol Otol 2010;124(02):166-170 2626 Andersen I, Camner P, Jensen PL, Philipson K, Proctor DF. A comparison of nasal and tracheobronchial clearance. Arch Environ Health 1974;29(05):290-293

Given the importance of MCC in lung defense, its evaluation is necessary as a contribution to the clinical and functional screening of the individual. Thus, as the STT test is a practical and effective evaluation method, the present literature review aims to provide basic information related to the STT test and to present the findings of previous studies that used this method, discussing variations in its execution, possible influences on the obtained results, and limitations of the method, besides relating our experience with the use of STT tests in research.

Review of a Particular Subject

The Method

The STT test was first described in 1974 by Andersen et al.2626 Andersen I, Camner P, Jensen PL, Philipson K, Proctor DF. A comparison of nasal and tracheobronchial clearance. Arch Environ Health 1974;29(05):290-293 It consisted of the insertion of a sodium saccharin particle on the upper surface of the inferior nasal turbinate of the subject. Next, the subjects were asked to swallow once every minute and to notify the examiner when they noticed a sweet taste. The distance from the start of the mucociliary membrane to the far wall of the pharynx was measured with a probe, and from this measurement the mean velocity was determined.

This method was modified by Rutland et al,2727 Rutland J, Cole PJ. Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis. Thorax 1981;36(09):654-658 who, prior to the evaluation, kept the subjects for at least an hour in an environmental temperature between 21 and 24°C, with relative humidity between 30 and 50%, and requested that the subjects blow their nose gently to remove any excess secretion. The saccharin particle was 0.5 mm in diameter and was placed in the inferior turbinate of one nasal cavity at least 7 mm behind the anterior end of the turbinate to avoid the area of mucosa where the cilia beat in an anterior direction. Another difference in this study lies in the fact that the subjects were not instructed to swallow regularly and that the distance between the particle placement and the nasopharynx was not measured. Therefore, only the time was obtained, but not the velocity of clearance.

Since then, the STT technique has been used in several studies involving MCC,1212 Oozawa H, Kimura H, Noda T, Hamada K, Morimoto T, Majima Y. Effect of prehydration on nasal mucociliary clearance in low relative humidity. Auris Nasus Larynx 2012;39(01):48-52 2222 Proença de Oliveira-Maul J, Barbosa de Carvalho H, Goto DM, et al. Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. Chest 2013;143(04):1091-1097 2424 Arnaoutakis D, Collins WO. Correlation of mucociliary clearance and symptomatology before and after adenoidectomy in children. Int J Pediatr Otorhinolaryngol 2011;75(10):1318-1321 2525 Naiboglu B, Deveci I, Kalaycik C, et al. Effect of nasolacrimal duct obstruction on nasal mucociliary transport. J Laryngol Otol 2010;124(02):166-170 2828 Proença M, Pitta F, Kovelis D, et al. Mucociliary clearance and its relation with the level of physical activity in daily life in healthy smokersandnonsmokers.RevPort Pneumol2012;18(05):233-238 either to characterize different populations1111 Ho JC, Chan KN, Hu WH, et al. The effect of aging on nasal mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia.AmJ Respir Crit CareMed 2001;163(04):983-988 2121 Plaza Valía P, Carrión Valero F, Marín Pardo J, Bautista Rentero D, González Monte C. [Saccharin test for the study of mucociliary clearance: reference values for a Spanish population]. Arch Bronconeumol 2008;44(10):540-545 2222 Proença de Oliveira-Maul J, Barbosa de Carvalho H, Goto DM, et al. Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. Chest 2013;143(04):1091-1097 2929 Stanley PJ, Wilson R, Greenstone MA, MacWilliam L, Cole PJ. Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency. Thorax 1986;41(07):519-523 3030 Wilson R, Sykes DA, Currie D, Cole PJ. Beat frequency of cilia from sites of purulent infection. Thorax 1986;41(06):453-458 or to evaluate the effect of interventions such as the use of anesthetics,3131 Bilgi M, Goksu S,Mizrak A, et al. Comparison of the effects of lowflow and high-flow inhalational anaesthesia with nitrous oxide and desflurane on mucociliary activity and pulmonary function tests. Eur J Anaesthesiol 2011;28(04):279-283 3232 Kesimci E, Bercin S, Kutluhan A, Ural A, Yamanturk B, Kanbak O. Volatile anesthetics and mucociliary clearance. Minerva Anestesiol 2008;74(04):107-111 continuous positive airway pressure (CPAP),55 Ferri RG, Zonato A, Guilherme A, et al. Análise do clearance mucociliar nasal e dos efeitos adversos do uso de CPAP. Rev Bras Otorrinolaringol 2004;70(02):150-155 3333 de Oliveira LR, Albertini Yagi CS, Figueiredo AC, Saldiva PH, Lorenzi-Filho G. Short-term effects of nCPAP on nasal mucociliary clearance and mucus transportability in healthy subjects. Respir Med 2006;100(01):183-185 and smoking cessation.3434 RamosEM, De Toledo AC, Xavier RF, et al. Reversibility of impaired nasal mucociliary clearance in smokers following a smoking cessation programme. Respirology 2011;16(05):849-855

However, differences are found in the execution of the technique among the published studies, related to the position of the subject, to the manner of introduction of the saccharin particle, to its size, and guidance to the subject being examined (Table 1).

Table 1
Methodological variations in saccharin transit time test in the literature

The pretest guidance found in the literature includes not ingesting alcoholic or caffeine-based substances, such as coffee, tea, soda, and energy drinks; drugs such as anesthetics, analgesics, barbiturates, tranquilizers, and antidepressants; not smoking for at least 12 hours; and not performing vigorous physical activities during the 12 hours preceding the test.2222 Proença de Oliveira-Maul J, Barbosa de Carvalho H, Goto DM, et al. Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. Chest 2013;143(04):1091-1097 3434 RamosEM, De Toledo AC, Xavier RF, et al. Reversibility of impaired nasal mucociliary clearance in smokers following a smoking cessation programme. Respirology 2011;16(05):849-855 3535 Alobid I, Enseñat J, Mariño-Sánchez F, et al. Impairment of olfaction and mucociliary clearance after expanded endonasal approach using vascularized septal flap reconstruction for skull base tumors. Neurosurgery 2013;72(04):540-546 3636 Priscilla J, Padmavathi R, Ghosh S, et al. Evaluation ofmucociliary clearance among women using biomass and clean fuel in a periurban area of Chennai: A preliminary study. Lung India 2011;28(01):30-33 3737 Delehaye E, Dore MP, Bozzo C, Mameli L, Delitala G, Meloni F. Correlation between nasal mucociliary clearance time and gastroesophageal reflux disease: our experience on 50 patients. Auris Nasus Larynx 2009;36(02):157-161 3838 Zhang L, Han D, Song X,Wang K,Wang H. Effect of oxymetazoline on healthy human nasal ciliary beat frequency measured with high-speed digital microscopy and mucociliary transport time. Ann Otol Rhinol Laryngol 2008;117(02):127-133 3939 Salah B, Dinh Xuan AT, Fouilladieu JL, Lockhart A, Regnard J. Nasal mucociliary transport in healthy subjects is slowerwhen breathing dry air. Eur Respir J 1988;1(09):852-855 4040 Gorpelioglu C, Ozol D, Sarifakioglu E. Influence of isotretinoin on nasal mucociliary clearance and lung function in patients with acne vulgaris. Int J Dermatol 2010;49(01):87-90 4141 Deniz M, Uslu C, Ogredik EA, Akduman D, Gursan SO. Nasal mucociliary clearance in total laryngectomized patients. Eur Arch Otorhinolaryngol 2006;263(12):1099-1104 4242 Isaacs S, Fakhri S, Luong A, Whited C, Citardi MJ. The effect of dilute baby shampoo on nasal mucociliary clearance in healthy subjects. Am J Rhinol Allergy 2011;25(01):e27-e29 4343 Rosen EJ, Calhoun KH. Alterations of nasalmucociliary clearance in association with HIV infection and the effect of guaifenesin therapy. Laryngoscope 2005;115(01):27-30 4444 Okuyucu S, Akoglu E, Oksuz H, Gorur H, Dagli S. The effect of dacryocystorhinostomy on mucociliary function. Otolaryngol Head Neck Surg 2009;140(04):585-588 4545 MiddletonPG,GeddesDM, AltonEW.Effect ofamiloride andsaline on nasal mucociliary clearance and potential difference in cystic fibrosis and normal subjects. Thorax 1993;48(08):812-816 4646 Unal M, Oz O, Adigüzel U, Vayisoglu Y, Vatansever H, Görür K. Mucociliary clearance after external dacryocystorhinostomy. Clin Otolaryngol Allied Sci 2004;29(03):264-265 4747 Cmejrek RC, Gutman MT, Torres AJ, Keen KJ, Houser SM. The effect of injection immunotherapy on mucociliary clearance in allergic patients. Otolaryngol Head Neck Surg 2005;133(01):9-15 4848 Boatsman JE, Calhoun KH, Ryan MW. Relationship between rhinosinusitis symptoms and mucociliary clearance time. Otolaryngol Head Neck Surg 2006;134(03):491-493 4949 Xavier RF, Ramos D, Ito JT, et al. Effects of cigarette smoking intensity on the mucociliary clearance of active smokers. Respiration 2013;86(06):479-485 5050 Altuntas EE, Kaya A, Uysal IO, Cevit Ö, Içagasioglu D, Müderris S. Anterior rhinomanometry and determination of nasal mucociliary clearance time with the saccharin test in children with Crimean-Congo hemorrhagic fever. J Craniofac Surg 2013;24 (03):e239-e242 5151 Develioglu ON, Sirazi S, TopakM, Purisa S, Kulekci M. Differences in Mucociliary activity of volunteers undergoing Ramadan versus Nineveh fasting. Eur Arch Otorhinolaryngol 2013;270 (05):1655-1659 5252 Bercin S, Ural A, Kutluhan A. Effects of topical drops and sprays on mucociliary transport time and nasal air flow. Acta Otolaryngol 2009;129(11):1257-1261 5353 Yoruk O, Ates O, Araz O, et al. The effects of silica exposure on upper airways and eyes in denim sandblasters. Rhinology 2008; 46(04):328-333 5454 Wolff RK, Dolovich MB, Obminski G, Newhouse MT. Effects of exercise and eucapnic hyperventilation on bronchial clearance in man. J Appl Physiol 1977;43(01):46-50

This guidance is given due to the fact that MCC changes in different conditions, such as age, level of physical activity in daily life, smoking, and use of drugs and other substances, such as caffeine and alcohol. Therefore, it is essential to consider these aspects and control them, when possible, before evaluating this lung defense mechanism.

The normality values for STT have been published for the Spanish population. Plaza Valía et al2121 Plaza Valía P, Carrión Valero F, Marín Pardo J, Bautista Rentero D, González Monte C. [Saccharin test for the study of mucociliary clearance: reference values for a Spanish population]. Arch Bronconeumol 2008;44(10):540-545 found a median of 16 minutes, and 50% of their results ranged from 12 to 20 minutes (interquartile interval). While these values can shed light on what can be expected as a result of this test, they might not be representative of other populations, with different ethnicities and living in different environmental conditions. To the best of our knowledge, there are no studies presenting reference values for other populations.

Factors that Influence MCC

Age

The respiratory system undergoes changes with advancing age, such as loss of lung elasticity, decrease in diaphragm strength, lung function decline, and an increase in the susceptibility to infections.2222 Proença de Oliveira-Maul J, Barbosa de Carvalho H, Goto DM, et al. Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. Chest 2013;143(04):1091-1097 Studies indicate that age also interferes with MCC.1111 Ho JC, Chan KN, Hu WH, et al. The effect of aging on nasal mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia.AmJ Respir Crit CareMed 2001;163(04):983-988 2222 Proença de Oliveira-Maul J, Barbosa de Carvalho H, Goto DM, et al. Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. Chest 2013;143(04):1091-1097 A correlation analysis has shown that MCC becomes progressively slower with advancing age, beginning at the early twenties,2121 Plaza Valía P, Carrión Valero F, Marín Pardo J, Bautista Rentero D, González Monte C. [Saccharin test for the study of mucociliary clearance: reference values for a Spanish population]. Arch Bronconeumol 2008;44(10):540-545 5555 Svartengren M, Falk R, Philipson K. Long-term clearance from small airways decreases with age. Eur Respir J 2005;26(04): 609-615 probably due to an increasing incidence of defects in the structure of the cilia.1111 Ho JC, Chan KN, Hu WH, et al. The effect of aging on nasal mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia.AmJ Respir Crit CareMed 2001;163(04):983-988

Septal Deviations

Kamani et al5656 Kamani T, Yilmaz T, Surucu S, Turan E, Brent KA. Scanning electron microscopy of ciliae and saccharine test for ciliary function in septal deviations. Laryngoscope 2006;116(04):586-590 have shown that young adults with septal deviations presented impaired MCC in both nostrils when compared with matched controls. When looking only at the study group, the concave (opposite side) presented even more impaired MCC than the convex side of the deviation. Therefore, this anatomical alteration might be considered an exclusion criterion for cross-sectional studies comparing different cohorts. In the case of longitudinal/interventional studies, it should be considered, a priori, whether this alteration could implicate possible bias in the findings.

Smoking

Smoking is an accelerator of lung function decline.5757 Rubin AS, Cavalazzi AC, Viegas CAA, et al. Diretrizes para testes de funçao pulmonar. J Bras Pneumol 2002;28(03):237 Besides interfering in the respiratory tract, it causes inflammation and mutagenic effects, which can result in the development of malignant neoplasias.5858 Koop CE, Luoto J. "TheHealth Consequences of Smoking: Cancer," overview of a report of the Surgeon General. Public Health Rep 1982;97(04):318-324 5959 Wattenberg EV. Noncarcinogenic effects of cigarette smoke on the respiratory tract. Environment Health Sci 2012;8:10 6060 Comandini A, Rogliani P,Nunziata A, CazzolaM, Curradi G, Saltini C. Biomarkers of lung damage associated with tobacco smoke in induced sputum. Respir Med 2009;103(11):1592-1613 Stanley et al2929 Stanley PJ, Wilson R, Greenstone MA, MacWilliam L, Cole PJ. Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency. Thorax 1986;41(07):519-523 evaluated the MCC of 29 smokers and of 27 nonsmokers and observed higher values of STT in the first group (20.8 ± 9.3 minutes) compared with the second (11.1 ± 3.8 minutes). More recently, Proença et al2323 Proença M, Fagundes Xavier R, Ramos D, Cavalheri V, Pitta F, Cipulo Ramos EM. [Immediate and short termeffects of smoking on nasal mucociliary clearance in smokers]. Rev Port Pneumol 2011;17(04):172-176 also observed a higher STT in smokers after 8 hours of abstinence (16 ± 6 minutes) compared with nonsmokers (10 ± 4 minutes). However, immediately after smoking, smokers presented a similar STT to nonsmokers (11 ± 6 minutes). Most likely, this represents an immediate defense response. Cigarette smoke leads to an increase in the ciliary beat frequency, probably as a consequence of the stimulation of sensory receptors from the epithelium or by the action of inflammatory mediators. Therefore, in addition to the chronic condition of smoking, the influence exerted by acute exposure to cigarette smoke should also be considered before evaluating MCC.

Physical Activity in Daily Life

Exercise is, in general, classified as a stressful stimulus,6161 Cannon JG, Meydani SN, Fielding RA, et al. Acute phase response in exercise. II. Associations between vitamin E, cytokines, and muscle proteolysis. Am J Physiol 1991;260(6 Pt 2):R1235-R1240 which can generate acute responses and chronic adaptations.6262 Nieman DC, Nehlsen-Cannarella SL. The immune response to exercise. Semin Hematol 1994;31(02):166-179 The first is associated with increased levels of adrenergic mediators,6363 Holmqvist N, Secher NH, Sander-Jensen K, Knigge U, Warberg J, Schwartz TW. Sympathoadrenal and parasympathetic responses to exercise. J Sports Sci 1986;4(02):123-128 and these stimulate ciliary beat frequency and, therefore, the MCC.6464 Devalia JL, Sapsford RJ, Rusznak C, Toumbis MJ, Davies RJ. The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells, in vitro. Pulm Pharmacol 1992;5(04):257-263 Proença et al2828 Proença M, Pitta F, Kovelis D, et al. Mucociliary clearance and its relation with the level of physical activity in daily life in healthy smokersandnonsmokers.RevPort Pneumol2012;18(05):233-238 evaluated the interference of physical activity in daily life in MCC and found that both nonsmokers and even light smokers with a high level of physical activity in daily life presented faster STTs than individuals with a less active or inactive lifestyle.

Ingested Substances

Some ingested substances also influence the functioning of MCC. It is known that a brief exposure to alcohol can quickly stimulate the cilia, through the production of nitric oxide and the activation of the kinase dependent protein, whereas prolonged exposure blocks the β-agonist stimulation of kinase protein activity and ciliary beating.66 Elliott MK, Sisson JH, Wyatt TA. Effects of cigarette smoke and alcohol on ciliated tracheal epithelium and inflammatory cell recruitment. Am J Respir Cell Mol Biol 2007;36(04):452-459 6565 Sisson JH. Alcohol and airways function in health and disease. Alcohol 2007;41(05):293-307

Caffeine consumption is related to autonomic modulation alteration resulting in an increased respiratory rate and bronchodilatation.6666 Monda M, Viggiano A, Vicidomini C, et al. Espresso coffee increases parasympathetic activity in young, healthy people. Nutr Neurosci 2009;12(01):43-48 6767 Yeragani VK, Krishnan S, Engels HJ, Gretebeck R. Effects of caffeine on linear and nonlinear measures of heart rate variability before and after exercise. Depress Anxiety 2005;21(03):130-134 It is known that MCC is also, at least in part, influenced by the autonomic system.5454 Wolff RK, Dolovich MB, Obminski G, Newhouse MT. Effects of exercise and eucapnic hyperventilation on bronchial clearance in man. J Appl Physiol 1977;43(01):46-50 It has been shown in humans that anticholinergic agents slow clearance,6868 Yeates DB, Aspin N, Levison H, Jones MT, Bryan AC. Mucociliary tracheal transport rates in man. J Appl Physiol 1975;39(03): 487-495 while cholinergic stimulation6969 Cammer P, Strandberg K, Philipson K. Increased mucociliary transport by cholinergic stimulation. Arch Environ Health 1974;29(04):220-224 and sympathomimetic agents speed clearance through changes in the ciliary beat frequency.6868 Yeates DB, Aspin N, Levison H, Jones MT, Bryan AC. Mucociliary tracheal transport rates in man. J Appl Physiol 1975;39(03): 487-495 7070 Foster WM, Bergofsky EH, Bohning DE, Lippmann M, Albert RE. Effect of adrenergic agents and their mode of action on mucociliary clearance in man. J Appl Physiol 1976;41(02):146-152

Drugs

Some drugs are employed for the purpose of changing MCC. Begrow et al7171 Begrow F, Böckenholt C, Ehmen M, Wittig T, Verspohl EJ. Effect of myrtol standardized and other substances on the respiratory tract: ciliary beat frequency and mucociliary clearance as parameters. Adv Ther 2012;29(04):350-358 observed that the use of standard Myrtol improved MCC in rats. Boek et al7272 Boek WM, Graamans K, Natzijl H, van Rijk PP, Huizing EH. Nasal mucociliary transport: new evidence for a key role of ciliary beat frequency. Laryngoscope 2002;112(03):570-573 found that MCC improved under the action of salbutamol, while it reduced under sodium chloride, and xylometazoline caused no significant change. Bercin et al5252 Bercin S, Ural A, Kutluhan A. Effects of topical drops and sprays on mucociliary transport time and nasal air flow. Acta Otolaryngol 2009;129(11):1257-1261 found that the topical nasal medications xylometazoline hydrochloride, fluticasone propionate, and seawater, which are often used without medical prescription, may worsen the MCC of individuals with nasal air flow lower than 500 ml and concluded that these drugs should be used carefully and selectively in patients with nasal complaints.

Other medications, which are not employed to act on MCC, can also cause alterations as a side effect. Houtmeyers et al7373 Houtmeyers E, Gosselink R, Gayan-Ramirez G, Decramer M. Effects of drugs on mucus clearance. Eur Respir J 1999;14(02): 452-467 conducted a review on the effects of routine clinical use of medications on MCC and concluded that anticholinergics (tertiary ammonium compounds), aspirin, anesthetics, and benzodiazepines (tranquilizers and anxiolytics) depress the MCC, probably by decreasing the ciliary beat frequency and mucus secretion. On the other hand, cholinergic agents, methylxanthines (theophylline, aminophylline, and bamifylline), sodium cromoglycate (anti asthmatic), antibiotics (those orally administered for chronic rhinosinusitis, such as penicillin, cephalosporin and sulfonamide), surfactant, hypertonic saline solution, and water aerosol improve the MCC, apparently by increasing the ciliary beat frequency and mucus secretion, and stimulating fluid secretion in the airway surface.

Circadian Cycle

The circadian cycle refers to rhythmic biological phenomena that occur in all forms of life and are influenced by the solar cycle (dark/light cycle) and by the environment. In humans, it is related to internal regulators of the central nervous system and interferes with the organization and sequencing of metabolic and physiological events, such as body temperature, blood hormone levels, urinary volume, cognitive and motor performance, sleep-wake cycle, and the breathing control system.7474 Moore RY. Circadian rhythms: basic neurobiology and clinical applications. Annu Rev Med 1997;48:253-266 7575 Stephenson R. Do circadian rhythms in respiratory control contribute to sleep-related breathing disorders? Sleep Med Rev 2003;7(06):475-490 7676 Mortola JP. Breathing around the clock: an overview of the circadian pattern of respiration. Eur J Appl Physiol 2004;91 (2-3):119-129 7777 McFadden ER Jr. Circadian rhythms. Am J Med 1988;85(1B):2-5 The upper and lower airways undergo normal cyclic changes; the size of the tracheobronchial tree decreases at night and increases during the day, and the venous erectile tissue of the nasal mucosa demonstrates normal cycles of congestion and constriction that cause alternations in the air flow from one nostril to the other over a period of several hours.

Environmental Conditions

Temperature, relative humidity, and altitude also interfere with MCC, as the nose, besides filtering the inhaled air, also participates in heating and humidification processes, ceding heat and water from its mucosa.7878 Sahin-Yilmaz A, Naclerio RM. Anatomy and physiology of the upper airway. Proc Am Thorac Soc 2011;8(01):31-39 7979 Cruz AA, Togias A. Upper airways reactions to cold air. Curr Allergy Asthma Rep 2008;8(02):111-117

Experimental and clinical studies have shown decreased MCC under environmental temperature changes8080 Kilgour E, Rankin N, Ryan S, Pack R. Mucociliary function deteriorates in the clinical range of inspired air temperature and humidity. Intensive Care Med 2004;30(07):1491-1494 8181 Proctor DF, Andersen I, Lundqvist GR. Human nasal mucosal function at controlled temperatures. Respir Physiol 1977;30 (1-2):109-124 due to increased mucus secretion by the nasal epithelium in order to facilitate heat exchange,7979 Cruz AA, Togias A. Upper airways reactions to cold air. Curr Allergy Asthma Rep 2008;8(02):111-117 and altered ciliary beat frequency, which is slower at lower temperatures.8282 Jorissen M, Bessems A. Influence of culture duration and ciliogenesis on the relationship between ciliary beat frequency and temperature in nasal epithelial cells. Eur Arch Otorhinolaryngol 1995;252(08):451-454 8383 Smith CM, Hirst RA, Bankart MJ, et al. Cooling of cilia allows functional analysis of the beat pattern for diagnostic testing. Chest 2011;140(01):186-190

Prolonged exposure to low humidity also results in greater dehydration of the nasal mucosa, which causes a change in the rheological properties of the mucus and impairs ciliary movements.3939 Salah B, Dinh Xuan AT, Fouilladieu JL, Lockhart A, Regnard J. Nasal mucociliary transport in healthy subjects is slowerwhen breathing dry air. Eur Respir J 1988;1(09):852-855 8484 Rodway GW, Windsor JS. Airway mucociliary function at high altitude. Wilderness Environ Med 2006;17(04):271-275

At high altitudes, both conditions, low humidity and temperature, are added together, submitting the respiratory system to a more hostile condition, in which MCC is also impaired.8484 Rodway GW, Windsor JS. Airway mucociliary function at high altitude. Wilderness Environ Med 2006;17(04):271-275

Studies of the Last Decade

Table 2 presents the studies published over the past 10 years in journals indexed in the PubMed and BIREME databases, written in English and Portuguese, found through the keywords mucociliary clearance and saccharin.

Table 2
Studies published in the last decade that employed the saccharin transit time test to evaluate mucociliary clearance

Experience Report

Considering the aspects that interfere in MCC mentioned in the literature, along with the experience acquired after years of use of STT in developed researches, our research group has standardized STT execution as follows:

Previous orientations: Request the patients to abstain from alcoholic substances, foods and beverages containing caffeine, cigarettes, and drugs for at least 12 hours prior to the evaluation and ask them not to perform strenuous physical activity the day before, as these are associated with increased levels of adrenergic mediators that stimulate the ciliary beat frequency, and thus the clearance.66 Elliott MK, Sisson JH, Wyatt TA. Effects of cigarette smoke and alcohol on ciliated tracheal epithelium and inflammatory cell recruitment. Am J Respir Cell Mol Biol 2007;36(04):452-459 5454 Wolff RK, Dolovich MB, Obminski G, Newhouse MT. Effects of exercise and eucapnic hyperventilation on bronchial clearance in man. J Appl Physiol 1977;43(01):46-50 6363 Holmqvist N, Secher NH, Sander-Jensen K, Knigge U, Warberg J, Schwartz TW. Sympathoadrenal and parasympathetic responses to exercise. J Sports Sci 1986;4(02):123-128 6464 Devalia JL, Sapsford RJ, Rusznak C, Toumbis MJ, Davies RJ. The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells, in vitro. Pulm Pharmacol 1992;5(04):257-263 6565 Sisson JH. Alcohol and airways function in health and disease. Alcohol 2007;41(05):293-307 6666 Monda M, Viggiano A, Vicidomini C, et al. Espresso coffee increases parasympathetic activity in young, healthy people. Nutr Neurosci 2009;12(01):43-48 6767 Yeragani VK, Krishnan S, Engels HJ, Gretebeck R. Effects of caffeine on linear and nonlinear measures of heart rate variability before and after exercise. Depress Anxiety 2005;21(03):130-134 If it is necessary to temporarily cease using any medication to perform the STT, the doctor should be consulted.

Evaluation scheduling: Ensure the subjects present clinic stability. If they are apparently healthy, consider a week free from fever, cough, and/or increased mucous production, since these are common symptoms of respiratory tract infections and it is known that this impairs MCC.8585 Fokkens WJ, Scheeren RA. Upper airway defence mechanisms. Paediatr Respir Rev 2000;1(04):336-341 For patients with lung disease, consider 30 days free from exacerbation.

It is essential that the same period of the day is chosen for the evaluations. It is preferable to schedule them in the morning, since the previous night, in most cases, the subjects sleep, and in these sleeping hours they do not make use of the substances previously described, making it easier to complete the required 12 hours of abstinence. In addition, in the first hours of the morning, subjects are normally exposed to environmental pollution for less time until the time of evaluation.

Preparation of the evaluation environment: The environment should be quiet, free from people flow and previously prepared to a maintained temperature of 25° C and to a relative humidity between 50 and 60%, since variations in these parameters interfere in the MCC.8080 Kilgour E, Rankin N, Ryan S, Pack R. Mucociliary function deteriorates in the clinical range of inspired air temperature and humidity. Intensive Care Med 2004;30(07):1491-1494

Required materials: For the preparation of the environment, an air conditioner unit and a humidifier are needed to ensure the required temperature and relative humidity.

For the placement of sodium saccharin, a plastic straw, trimmed to facilitate the deposition of particles inside the nostril, (Fig. 1A) should be used.

Fig. 1
Saccharin transit time test materials and execution.

The amount of introduced saccharin is standardized as 2.5 micrograms, which corresponds to ∼ 5 particles of the substance.

Execution of the STT test: Subjects are in a sitting position, with the head supported in a slight extension (∼ 10° neck extension) (Fig. 1B).

The placement of saccharin is performed under visual control, 2 cm into the inferior turbinates of the right nostril of the subjects. The right nostril is chosen as a way of standardizing and facilitating the reproduction of the method.

Subjects are asked to maintain their natural breathing and swallowing and not to get up, talk, cough, sneeze, or manipulate their nose. If this happens, the test is cancelled and rescheduled for another day. These guidelines are to prevent the change in airflow or mechanical touches from modifying the movement of the particles and interfering with the test results.

The expected flavor and nature of the substance should not be disclosed to prevent false positives.

Limitations of the Method

Despite subjects being instructed on how to breathe and swallow, these aspects are not objectively controlled by the evaluators and can vary among volunteers.

The test does not present visible results for evaluators, who take the report of the subjects as true. One way to avoid a false positive is not revealing the real flavor of the substance to be perceived by the subject, so the result is more reliable.

Even though saccharin presents a strong taste, its perception is subjective and may vary among subjects, and it is possible that some of them present altered taste, which would interfere in the results, not due to MCC conditions, but to individual taste perception.

The placement of saccharin, although not invasive, requires great attention and some manual skill training from the evaluator, since anatomical differences may hinder the insertion of the particle and even interfere with the exact location of deposition.

Cleaning the nostrils before the evaluation may be helpful to avoid possible additional mechanical barriers to the passage of the particle. However, the act of blowing the nose of the subject can interfere with the MCC due to the change in airflow.

Discussion

The STT test is an effective and widely used method in scientific research related to nasal MCC, which is essential in maintaining the health of the respiratory system. However, despite its simple implementation, some care is necessary to guarantee reliable results. In addition, a standardization of the application protocol is recommended so that future comparisons between different studies employing STT become possible in a reliable way.

The factors that can interfere with the results obtained by the STT test are worth highlighting: age, temperature, circadian cycle, presence of infections, use of drugs, of caffeine-based or of alcoholic substances, presence and intensity of smoking as well time of abstinence, physical exercise performance, and level of physical activity in daily life.

Final Comments

It is concluded that STT test is a widely used method for evaluation of nasal MCC, and, therefore, a standardization related to prior and concurrent test guidelines to professionals as well as to their execution is essential to improve the accuracy of the test, and to allow comparisons among different studies that employ it.

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Publication Dates

  • Publication in this collection
    18 July 2019
  • Date of issue
    Apr-Jun 2019

History

  • Received
    23 Jan 2018
  • Accepted
    06 Oct 2018
  • Published
    15 Feb 2019
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