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Measurement of nasal mucosal blood flow
Editorial Measurement of nasal mucosal blood flow
The responses of the nose to exogenous stimuli, such as pollens, dusts, viruses, cold air, or hot food, are limited to symptoms produced by the nasal mucosa. These include sneezing and itching, increase or decrease in nasal secretion, and nasal obstruction. ~Of these, the last is of considerable interest. Clinically, nasal obstruction is the most difficult of the symptoms to treat, not being amenable to conventional antihistamine therapy and may be the most bothersome to patients, as it impedes breathing, z Attempts have been made to quantify the degree of nasal obstruction, although it is well recognized that an objective measurement of airflow resistance may bear little relationship to subjective sensation of blockage)' 4 Techniques have included breathing onto a mirror, xerography, 5 optical measurements, 6 measurements of inspiratory or expiratory flow, 7 plethysmography, 8 computed tomography scanning, 9 and the flow/pressure measurements of rhinomanometry. ~o Despite advances in rhinomanometric techniques,~,. ~2 airflow resistance measurements do not yield physiologic information on the cause of the nasal obstruction. It has been generally accepted that increases in this obstruction are caused by transient engorgement of the capacitance sinasoids located deep in the nasal mucosa. ~~There is good reason to believe that this is an oversimplification. First, in chronic rhinitis with nasal obstruction, oral vasoconstrictors (primarily a-adrenergic agonists) are poorly effectiveJ 4 Second, visible decongestion has been observed in the absence of NMBF changes.* Third, cellular infiltration, such as occurs in the mast cellmediated "late-phase reaction" is believed to play a significant role in the nasal obstruction of chronic allergic rhinitis. '5' 16 Furthermore, increase in secretions, especially with crusting and synechiae bridging the narrow portions of the nasal cavity, contribute to
Fromthe Divisionof Allergyand Immunology,St. LouisUniversity School of Medicine, St. Louis, Mo. Reprint requests: HowardM. Druce, MD, Divisionof Allergyand Immunology.St. Louis UniversitySchool of Medicine, 1402 S. Grand Blvd. St. Louis, MO 63104. *Druce HM. Unpublished observations.
Abbreviations used
LDV: NMBF: NPC: XW:
Laser-Doppler velocimetu' Nasal mucosal blood flow Nasal provocation challenge Xenon washout
an elevated nasal airway resistance, It is also plausible that changes in tissue edema contribute to increased volume of mucosal tissue.'7 For these reasons, attempts have been made to separate the components of nasal airway resistance and analyze them independently. Measurement of NMBF is not a new concept, and the literature is full of examples of studies, prompted by novel advances in technology. Initially, simple observations of mucosal color were followed by colorimetry. Various other techniques, such as thermal conductivity, have been applied? s" ~9In animals, invasive studies with radioactive microspheres z~ and vessel cannulation are feasible but are less applicable to human use. ~" Currently, three techniques are in active use for human measurements. These are radioactive X W ] ~ hydrogen clearance, 22 and LDV. > ~" The article by Holmberg et ai~, -'5 in this issue of the JOURNAL, describes a study in which the response of mucosal blood flow to topical NPC with antigen was measured by the XW technique. The data indicate a dose-dependent decrease in flow after bilateral nasal challenge with increasing doses of antigen. The highest dose of antigen produced a 2 3 ~ decrease in blood flow. Maximal changes occurred l0 to 20 minutes after challenge, followed by a gradual return to baseline. Challenge to one nostril also produced a decrease in blood flow in the contralaterat, unch~dlenged nasal cavity. These findings are intriguing in the light of other recent data. Bende et a156 also demonstrated a fall in NMBF after antigen challenge, as determined by XW. However, Juliusson and Bende 2"J demonstrated an increase in flow after antigen challenge, as measured 505
506 Druce
by LDV, and increases in blood flow after histamine challenge. Olanoff et al. z8also demonstrated increases in NMBF after histamine provocation, Why should such variations occur? First, the data suggest that, although histamine may be the major chemical mediator producing symptoms in the acute allergic reaction, it may not be the most significant agent producing vasoactive effects. Second, each method of measurement of NMBF carries its own methodologic limitations. For XW studies, the isotope has to be injected into the mucosa, z9 This is usually done with an 0.1 ml solution through a small gauge needle without anesthesia. Although the inferior turbinate mucosa is not especially sensitive, clearly, neural receptors are activated, and tissues are distended by the injected fluid. Indeed, blood vessels may be punctured, as Holmberg et al. 25 note. The numerical value of the data obtained depends on the partition coefficient of xenon between blood and mucosa. This factor has not been specifically verified for nasal tissue. In addition, this method involves introduction of allergens in the sitting position, but measurements are made with the subject supine. It has been welt described that changes in posture induce significant changes in nasal airway resistance, 3° and possibly also in NMBF. 3~ Hydrogen clearance measurements have been demonstrated to manifest variations similar to those obtained with XW. However, only one study that used this technique in the nose has been presented to date. 32 Antigen provocation challenge was delivered by antigen-soaked paper disks placed on the inferior turbinates. Blood flow was found to be reduced close to the area of contact of the disk but was increased in an area 10 mm distant. The technique of LDV (termed flowmetry in Europe) avoids the need for injection of the mucosa, since a recording probe is placed gently against the turbinate surface without need for pressure contact. 33 Continuous readings over time may be obtained, and in the application developed by the author, no changes in posture are involved from the time of antigen challenge to obtaining measurements. The validity of the data depends on an acceptance of the laser-Doppler theory. ~4The physical measurements obtained may be converted to units of milliliters per 100 gm of tissue per minute by a conversion factor?8 This factor has been computed for tissues with a density similar to that of nasal mucosa, but not directly on nasal tissue. Movement artifact is a potential problem when a lightemitting probe has to remain in contact with tissue for a period of up to 1 hour. Only one instrument has been used that addresses this problem by incorporating
J. ALLERGY CLIN, IMMUNOL. MARCH 1988
a reference beam that records reflected light intensity. 33 Microcirculatory parameters other than flow can be measured. When high speed arteriovenous shunt or resistance vessels are predominant (eg, in a decongested nose), the flow is a significant limiting determinant of response. However, once the nose becomes congested, the volume of tissue occupied by blood is also an important factor. Of the three current methods, only LDV has the capability to measure blood volume. In addition, the continuous nature of LDV recording permits measurement of flow pulsatility. The latter is produced by a combination of spontaneous vasomotion in the tissue bed and systolic/diastolic variations. The significance of pulsatility measurements is as yet unclear, but it may have relevance in studies determining tissue perfusion. 35"38 Since the introduction of antigens induces significant mucosal edema, it is perhaps desirable that parameters other than flow rates be considered. Not only can mechanical effects reduce flow25 but also edema may lead to diversion of blood away from the more superficial mucosal areas that are being studied. Regardless of the method used, the intrinsic variability of NMBF cannot be escaped. Since the flow rate is designed to adapt to changes in ambient temperature and relative humidity, 39,40 this is hardly surprising. Thus, strict attention must be paid in keeping baseline conditions as stable as possible. Control data must be obtained for each subject, as well as response to diluents and vehicles. Superimposed on a large baseline variability2s is the error associated with the sensitivity of the system. Probe placement in a less vascular location and injection technique variations should be accounted for by control data. With the LDV system, repetitive challenges with saline led to an average 15% fall in mucosal blood flow; hence, it was considered that only changes in excess of this can be considered significant? 3 The maximal inherent "noise" in the XW and hydrogen systems has not been well described. Ideally, parallel studies should be performed to compare different measurement systems. Studies comparing nasal airway resistance and XW data have yielded a less than perfect correlation, as have comparisons between XW and LDVf" 42 However, since different parameters are being compared, this discrepancy is not surprising. Some comparative studies may not be feasible logistically, and limitations include the time required to develop proficiency in each technique and the funding required for equipment and training. Ideally, each method should be compared with a reference standard that would probably require
VOLUME 81 NUMBER 3
M e a s u r e m e n t of nasal m u c o s a ! bio,-~d ~iow
invasive instrumentation? 3'44 However, invasive techniques for blood flow measurement are not sensitive to purely mucosal flow. 4~ How important are blood flow measurements? Other than as an adjunct to monitoring antigen NPC, there are several potential applications. The human nasal mucosa is the only human mucous membrane mounted, as it were, on a rigid platform and thus amenable to a variety of quantitative procedures. It is thus a model for penetration not only of antigens but also of nonspecific pollutants and drugs. The latter, if they are receptor specific, can act as selective probes to study pathophysiologic mechanisms. For example, neurohormone analogs, such as methacholine (cholinergic) and phenylephrine (a-adrenergic), may be introduced with and without specific antagonists. 46' 47 Histamine challenge may mimic one arc of the acute allergic response and the specificity of the challenge verified by antihistamine blockade. 4s Neurophysiologic variations, such as the nasal cycle, 49 have not been verified by NMBF measurements. Clearly, measurements of NMBF are of great interest to the allergist and physiologist. No one method used to date can be described as clearly superior, and further refinements of technique and novel technologies can be expected. Research studies need to incorporate larger population sample sizes to address the problem of baseline variability. The data will have to be viewed with care until results reported by different laboratories are consistent. The technique is still far from being useful as a clinical tool. Finally, every investigator in this field should be prepared to address the methodologic limitations of each technique.
Howard M. Druce, MD Division of Allergy and Immunology St. Louis UniversiO, School of Medicine 1402 S. Grand Blvd. St. Louis, MO 63104 l thank Vernon Fischer, PhD, for his editorial suggestions, and Margaret Smith for typing the manuscript. REFERENCES
1. Druce HM. Nasal physiology. Ear Nose Throat J 1986;65: 201-5. 2. Myer CM III, Cotton RT. Nasal obstruction in the pediatric patient. Pediatrics 1983;72:766-77. 3. Ecctes R, Lancashire B, Tolley NS. Experimental studies on nasal sensation of airflow. Aeta Otolaryngol 1987;103:303-6. 4. Jones AS, Lancer JM, Shone G, Stevens JC. The effect of lignocaine on nasal resistance and nasal sensation of airflow. Acta Otolaryngol 1986;101:328-30. 5. Murgolo VJ, Bickham CE Jr. Xeroradiography for evaluating and analyzing nasal patency. Eye Ear Nose Throat Mon 1974;53:425-30.
507
6, Juto J-E, Lundberg C Variation in nasal rout ~sa co~geqion during rest. Acta Orolaryngol 1984;98:136-9. 7. Cockcroft DW, MacCormack DW, Tarto SM, }-largreave FE, Pengelly LD, Nasal airway inspirator?~ resuscitate. Am Rev Respir Dis 1979;t 19:921--6. 8. Gherson G, Moscato G, Vidi 1, Salvaterra ',, Candura F. Nonspecific nasal reactivity: a proposed meth<~! o ' ~,mdy Eur J Respir Dis 1986;69:24-8. 9, Chinwuba C, Wallman J, Strand R, Nasal airv,~:~yobstruction: CT assessment. Radiology 1986;159:503-6, 10. Solomon WR, Mclean JA. Nasal provocative te~ting. In: Spector SL, ed. Provocative challenge procedures: bronchial, oral nasal and exercise, ~'ol. 2, Boca Raton. F!':: CRC Press, 1983: 133-67. 1t~ Cole P, Fastag O, Niinimaa V. Cornputer-ai~ied rhinometry. Acta Otolaryngol 1980:139-42_ 12, Kern EB. Committee report on standardization of rhinoman-. ometry. Rhinology 1981;19:23t-6, 13. Bemstein JM, Immunological and nonimmunoiogicat mechanisms in nasal hyperreactivity, hnmun(~f Allergy Pracr 1985;7:160-9. 14, Mygind N. Pharmacotherapy of nasal diseas,~ NER Allergy Proc 1985;6:245-48. 15. Dvoracek JE, Yunginger JW, Kern FB, Hyatt RE~ Gleich G J. Induction of nasal late-phase reactions by insufflation ot' ragweed-pollen extract. J ALLERGY(?l,~t~ l,~,,~t!,~O!, t984:73: 363-8, 16, Kaliner M. Hypotheses on the contribution of late-phase Ntergic responses to the understanding and treatment of allergic diseases. J ALLERGYCUN IMMUNOL1984;73:31 I' I5. 17. Proctor DF, Adams GK III. Physiology ,and pharmacok,'gy of nasal function and mucus secretion Pharmac Ther [B] 1976;2:493-509. 18. Nitzan M, Brama I, Mahler Y, Measurement of nasal mucosal blood flow by a thermal clearance method IEEE T?ans Biomed Eng t985;32 t2:1063-66. 19. Kumlein J, Perbeck L. Fluourescein flowmetr~ in human nasal mucosa. Acta Otolaryngol 1986;101:286-9. 20. Abe Y, Jackson RT. The use of labeled micmspheres to determine blood flow in the dog's nasal mt~cos;~ Ann Otol 1972;8t:82-6. 21. Sejrsen P Blood flow in cutaneous tissue m man studied by washout of radioactive xenon. Circ Res 1969;25;215-29, 22, Aukland K, Bower BF, Berliner RW, Meast~rement of local blood flow with hydrogen gas. Circ Res 1964;14:164-87, 23. Stern MD, Lappe DL, Bowen PD, Chimosky ,lEo Hotloway GA Jr, Keiser HR, Bowman RL, Continuous, measurement of tissue blood flow by laser-Doppler spectroscopy. Am J Physiol 1977:232:H44t-8. 24. Olsson E Bende M, Ohlin P. The laser-Doppler ~lowmeter lot measuring microcirculation in human nasal mucosa, Acta Otolaryngol 1985;99:133-9. 25. Holmberg K, Bake B, Pipkorn U. Nasal mucosai blood flow after intranasal allergen challenge. J ALI,ER("~"CIIN IMMUNOL t988;81:54t-7, 26. Bende M, Elner A, Ohlin P. The effect of provoked allergic reaction and histamine on nasal mucosal blood flow in humans. Acta Ototaryngol 1984;97:99-104. 27. Juliusson S, Bende M. Allergic reaction of the human nasm mucosa studied with laser-Doppler flowme~. Clin Allergy 1987:17:301-5. 28. Olanoff LS, Titus CR, Sbea MS~ Gibson RE, Brooks CD. Effect of intranasal histamine on nasal muco~al bl~xqdflow and
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29.
30. 31.
32.
33.
34.
35.
36. 37.
38.
Druce
J. ALLERGYCLIN, IMMUNOL MARCH 1988
the antidiuretic activity of desmopressin. J Clin Invest 1987;80:890-5. Bende M, Flisberg K, Larsson I, Ohlin P, Olsson P. A method for determination of blood flow with ~33Xe in human nasal mucosa. Acta Otolaryngol 1983;96:277-85. Cole E Halght JSJ. Posture and nasal patency. Am Rev Respir Dis 1984;129:351-4. Bende M. Blood flow with ~33Xein human nasal mucosa in relation to age, sex, and body position. Acta Otolaryngol 1983;96:175-9. Tanimoto H, Okuda M, Yagi T, Ohtsuka H. Measurement of the blood flow of the nasal mucosa by the hydrogen clearance method. Rhinology 1983;21:59-65. Druce HM, Bonner RF, Patow C, Choo P, Summers ILl, Kaliner MA. Response of nasal blood flow to neurohormones as measured by laser-Doppler velocimetry. J Appl Physiol 1984;57(4):1276-83. Bonner RF, Clem TR, Bowen PD, Bowman RL. LaserDoppler continuous real-time monitor of putsatile and mean blood flow in tissue microcircutation. In: Chen SH, Chu B, Nossal R, eds. Scattering techniques applied to supramolecular and nonequilibrium systems. New York: Plenum, 1981:685-702. Mellander S, Johansson B. Control of resistance, exchange, and capacitance functions in the peripheral circulation. Pharmacol Rev 1968;20: 117-96. Rothe CF. Reflex control of veins and vascular capacitance. Physiol Rev 1983;63:1281-1342. Intaglietta M. Vasomotor activity, time-dependent fluid exchange, and tissue pressure. Microvasc Res 1981;21:15364. Salathe EP, Venkataraman R, Gross JE Microcirculatory response to periodic pulsations in capillary pressure. Microvasc Res 1982;24:272-95.
39. Mygind N. Nasal allergy. 2rid ed. Oxford: Blackwell, chap 9, 1979:140-54. 40. Cole P. Modification of inspired air. In: Proctor DF, Andersen I, eds. The nose: upper airway physiology and the atmospheric environment. Amsterdam: Elsevier, 1982:351-75. 41. Engelhart M, Kristensen JK. Evaluation of cutaneous blood flow responses by 133Xewashout and a laser-Doppler flowmeter. J Invest Dermatol 1983;80:12-15. 42. Olsson P. A comparison between the 133Xewashout and laserDoppler techniques for estimation of nasal mucosal blood flow in humans. Acta Otolaryngol 1986;102:106-12. 43. Pleschka K, Sugahara M, Hashimoto M, Sommerlad V, Lurkens I, Ernst C. Local circulatory control in thermal stress. In: Dejours P, ed. Comparative physiology of environmental adaptations, vol 2. Eighth ESCP Conference, Strasbourg, 1986. Basel: S Karger AG, 1987:107-22. 44. Smits GJ, Roman RJ, Lombard JH. Evaluation of laserDoppler flowmetry as a measure of tissue blood flow. J Appl Physiol 1986;61(2):666-72. 45. Anggard A, Edwalt L. The effects of sympathetic nerve stimulation on the tracer disappearance rate and local blood content in the nasal mucosa of the cat. Acta Otolaryngol 1974;77: 131-9. 46. Andersson K-E, Bende M. Adrenoceptors in the control of human nasal mucosal blood flow. Ann Otol Rhinol Laryngol 1984;93:179-82. 47. Settipane GA. Allergic rhinitis update. Otolaryngol Head Neck Surg 1986;94:470-5. 48. Togias AG, Naclerio RM, Warner J, Proud D, Kagey-Sobotka A, Nimmagadda I, Norman PS, Lichtenstein LM. Demonstration of inhibition of mediator release from human mast cells by azatadine base. JAMA 1986;255:225-9. 49. Stoksted P. Rhinometric measurements for determination of the nasal cycle. Acta Otolaryngol 1953;109(suppl):159-75.
Bound volumes available to subscribers Bound volumes of THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY are available to subscribers (only) for the 1988 issues from the Publisher, at a cost of $41.00 ($52.00 international) for Vol. 81 (January-June) and Vol. 82 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Co., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO 63146; phone (800) 325-4177, ext. 351.
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The responses of the nose to exogenous stimuli, such as pollens, dusts, viruses, cold air, or hot food, are limited to symptoms produced by the nasal mucosa. These include sneezing and itching, increase or decrease in nasal secretion, and nasal obstruction. ~Of these, the last is of considerable interest. Clinically, nasal obstruction is the most difficult of the symptoms to treat, not being amenable to conventional antihistamine therapy and may be the most bothersome to patients, as it impedes breathing, z Attempts have been made to quantify the degree of nasal obstruction, although it is well recognized that an objective measurement of airflow resistance may bear little relationship to subjective sensation of blockage)' 4 Techniques have included breathing onto a mirror, xerography, 5 optical measurements, 6 measurements of inspiratory or expiratory flow, 7 plethysmography, 8 computed tomography scanning, 9 and the flow/pressure measurements of rhinomanometry. ~o Despite advances in rhinomanometric techniques,~,. ~2 airflow resistance measurements do not yield physiologic information on the cause of the nasal obstruction. It has been generally accepted that increases in this obstruction are caused by transient engorgement of the capacitance sinasoids located deep in the nasal mucosa. ~~There is good reason to believe that this is an oversimplification. First, in chronic rhinitis with nasal obstruction, oral vasoconstrictors (primarily a-adrenergic agonists) are poorly effectiveJ 4 Second, visible decongestion has been observed in the absence of NMBF changes.* Third, cellular infiltration, such as occurs in the mast cellmediated "late-phase reaction" is believed to play a significant role in the nasal obstruction of chronic allergic rhinitis. '5' 16 Furthermore, increase in secretions, especially with crusting and synechiae bridging the narrow portions of the nasal cavity, contribute to
Fromthe Divisionof Allergyand Immunology,St. LouisUniversity School of Medicine, St. Louis, Mo. Reprint requests: HowardM. Druce, MD, Divisionof Allergyand Immunology.St. Louis UniversitySchool of Medicine, 1402 S. Grand Blvd. St. Louis, MO 63104. *Druce HM. Unpublished observations.
Abbreviations used
LDV: NMBF: NPC: XW:
Laser-Doppler velocimetu' Nasal mucosal blood flow Nasal provocation challenge Xenon washout
an elevated nasal airway resistance, It is also plausible that changes in tissue edema contribute to increased volume of mucosal tissue.'7 For these reasons, attempts have been made to separate the components of nasal airway resistance and analyze them independently. Measurement of NMBF is not a new concept, and the literature is full of examples of studies, prompted by novel advances in technology. Initially, simple observations of mucosal color were followed by colorimetry. Various other techniques, such as thermal conductivity, have been applied? s" ~9In animals, invasive studies with radioactive microspheres z~ and vessel cannulation are feasible but are less applicable to human use. ~" Currently, three techniques are in active use for human measurements. These are radioactive X W ] ~ hydrogen clearance, 22 and LDV. > ~" The article by Holmberg et ai~, -'5 in this issue of the JOURNAL, describes a study in which the response of mucosal blood flow to topical NPC with antigen was measured by the XW technique. The data indicate a dose-dependent decrease in flow after bilateral nasal challenge with increasing doses of antigen. The highest dose of antigen produced a 2 3 ~ decrease in blood flow. Maximal changes occurred l0 to 20 minutes after challenge, followed by a gradual return to baseline. Challenge to one nostril also produced a decrease in blood flow in the contralaterat, unch~dlenged nasal cavity. These findings are intriguing in the light of other recent data. Bende et a156 also demonstrated a fall in NMBF after antigen challenge, as determined by XW. However, Juliusson and Bende 2"J demonstrated an increase in flow after antigen challenge, as measured 505
506 Druce
by LDV, and increases in blood flow after histamine challenge. Olanoff et al. z8also demonstrated increases in NMBF after histamine provocation, Why should such variations occur? First, the data suggest that, although histamine may be the major chemical mediator producing symptoms in the acute allergic reaction, it may not be the most significant agent producing vasoactive effects. Second, each method of measurement of NMBF carries its own methodologic limitations. For XW studies, the isotope has to be injected into the mucosa, z9 This is usually done with an 0.1 ml solution through a small gauge needle without anesthesia. Although the inferior turbinate mucosa is not especially sensitive, clearly, neural receptors are activated, and tissues are distended by the injected fluid. Indeed, blood vessels may be punctured, as Holmberg et al. 25 note. The numerical value of the data obtained depends on the partition coefficient of xenon between blood and mucosa. This factor has not been specifically verified for nasal tissue. In addition, this method involves introduction of allergens in the sitting position, but measurements are made with the subject supine. It has been welt described that changes in posture induce significant changes in nasal airway resistance, 3° and possibly also in NMBF. 3~ Hydrogen clearance measurements have been demonstrated to manifest variations similar to those obtained with XW. However, only one study that used this technique in the nose has been presented to date. 32 Antigen provocation challenge was delivered by antigen-soaked paper disks placed on the inferior turbinates. Blood flow was found to be reduced close to the area of contact of the disk but was increased in an area 10 mm distant. The technique of LDV (termed flowmetry in Europe) avoids the need for injection of the mucosa, since a recording probe is placed gently against the turbinate surface without need for pressure contact. 33 Continuous readings over time may be obtained, and in the application developed by the author, no changes in posture are involved from the time of antigen challenge to obtaining measurements. The validity of the data depends on an acceptance of the laser-Doppler theory. ~4The physical measurements obtained may be converted to units of milliliters per 100 gm of tissue per minute by a conversion factor?8 This factor has been computed for tissues with a density similar to that of nasal mucosa, but not directly on nasal tissue. Movement artifact is a potential problem when a lightemitting probe has to remain in contact with tissue for a period of up to 1 hour. Only one instrument has been used that addresses this problem by incorporating
J. ALLERGY CLIN, IMMUNOL. MARCH 1988
a reference beam that records reflected light intensity. 33 Microcirculatory parameters other than flow can be measured. When high speed arteriovenous shunt or resistance vessels are predominant (eg, in a decongested nose), the flow is a significant limiting determinant of response. However, once the nose becomes congested, the volume of tissue occupied by blood is also an important factor. Of the three current methods, only LDV has the capability to measure blood volume. In addition, the continuous nature of LDV recording permits measurement of flow pulsatility. The latter is produced by a combination of spontaneous vasomotion in the tissue bed and systolic/diastolic variations. The significance of pulsatility measurements is as yet unclear, but it may have relevance in studies determining tissue perfusion. 35"38 Since the introduction of antigens induces significant mucosal edema, it is perhaps desirable that parameters other than flow rates be considered. Not only can mechanical effects reduce flow25 but also edema may lead to diversion of blood away from the more superficial mucosal areas that are being studied. Regardless of the method used, the intrinsic variability of NMBF cannot be escaped. Since the flow rate is designed to adapt to changes in ambient temperature and relative humidity, 39,40 this is hardly surprising. Thus, strict attention must be paid in keeping baseline conditions as stable as possible. Control data must be obtained for each subject, as well as response to diluents and vehicles. Superimposed on a large baseline variability2s is the error associated with the sensitivity of the system. Probe placement in a less vascular location and injection technique variations should be accounted for by control data. With the LDV system, repetitive challenges with saline led to an average 15% fall in mucosal blood flow; hence, it was considered that only changes in excess of this can be considered significant? 3 The maximal inherent "noise" in the XW and hydrogen systems has not been well described. Ideally, parallel studies should be performed to compare different measurement systems. Studies comparing nasal airway resistance and XW data have yielded a less than perfect correlation, as have comparisons between XW and LDVf" 42 However, since different parameters are being compared, this discrepancy is not surprising. Some comparative studies may not be feasible logistically, and limitations include the time required to develop proficiency in each technique and the funding required for equipment and training. Ideally, each method should be compared with a reference standard that would probably require
VOLUME 81 NUMBER 3
M e a s u r e m e n t of nasal m u c o s a ! bio,-~d ~iow
invasive instrumentation? 3'44 However, invasive techniques for blood flow measurement are not sensitive to purely mucosal flow. 4~ How important are blood flow measurements? Other than as an adjunct to monitoring antigen NPC, there are several potential applications. The human nasal mucosa is the only human mucous membrane mounted, as it were, on a rigid platform and thus amenable to a variety of quantitative procedures. It is thus a model for penetration not only of antigens but also of nonspecific pollutants and drugs. The latter, if they are receptor specific, can act as selective probes to study pathophysiologic mechanisms. For example, neurohormone analogs, such as methacholine (cholinergic) and phenylephrine (a-adrenergic), may be introduced with and without specific antagonists. 46' 47 Histamine challenge may mimic one arc of the acute allergic response and the specificity of the challenge verified by antihistamine blockade. 4s Neurophysiologic variations, such as the nasal cycle, 49 have not been verified by NMBF measurements. Clearly, measurements of NMBF are of great interest to the allergist and physiologist. No one method used to date can be described as clearly superior, and further refinements of technique and novel technologies can be expected. Research studies need to incorporate larger population sample sizes to address the problem of baseline variability. The data will have to be viewed with care until results reported by different laboratories are consistent. The technique is still far from being useful as a clinical tool. Finally, every investigator in this field should be prepared to address the methodologic limitations of each technique.
Howard M. Druce, MD Division of Allergy and Immunology St. Louis UniversiO, School of Medicine 1402 S. Grand Blvd. St. Louis, MO 63104 l thank Vernon Fischer, PhD, for his editorial suggestions, and Margaret Smith for typing the manuscript. REFERENCES
1. Druce HM. Nasal physiology. Ear Nose Throat J 1986;65: 201-5. 2. Myer CM III, Cotton RT. Nasal obstruction in the pediatric patient. Pediatrics 1983;72:766-77. 3. Ecctes R, Lancashire B, Tolley NS. Experimental studies on nasal sensation of airflow. Aeta Otolaryngol 1987;103:303-6. 4. Jones AS, Lancer JM, Shone G, Stevens JC. The effect of lignocaine on nasal resistance and nasal sensation of airflow. Acta Otolaryngol 1986;101:328-30. 5. Murgolo VJ, Bickham CE Jr. Xeroradiography for evaluating and analyzing nasal patency. Eye Ear Nose Throat Mon 1974;53:425-30.
507
6, Juto J-E, Lundberg C Variation in nasal rout ~sa co~geqion during rest. Acta Orolaryngol 1984;98:136-9. 7. Cockcroft DW, MacCormack DW, Tarto SM, }-largreave FE, Pengelly LD, Nasal airway inspirator?~ resuscitate. Am Rev Respir Dis 1979;t 19:921--6. 8. Gherson G, Moscato G, Vidi 1, Salvaterra ',, Candura F. Nonspecific nasal reactivity: a proposed meth<~! o ' ~,mdy Eur J Respir Dis 1986;69:24-8. 9, Chinwuba C, Wallman J, Strand R, Nasal airv,~:~yobstruction: CT assessment. Radiology 1986;159:503-6, 10. Solomon WR, Mclean JA. Nasal provocative te~ting. In: Spector SL, ed. Provocative challenge procedures: bronchial, oral nasal and exercise, ~'ol. 2, Boca Raton. F!':: CRC Press, 1983: 133-67. 1t~ Cole P, Fastag O, Niinimaa V. Cornputer-ai~ied rhinometry. Acta Otolaryngol 1980:139-42_ 12, Kern EB. Committee report on standardization of rhinoman-. ometry. Rhinology 1981;19:23t-6, 13. Bemstein JM, Immunological and nonimmunoiogicat mechanisms in nasal hyperreactivity, hnmun(~f Allergy Pracr 1985;7:160-9. 14, Mygind N. Pharmacotherapy of nasal diseas,~ NER Allergy Proc 1985;6:245-48. 15. Dvoracek JE, Yunginger JW, Kern FB, Hyatt RE~ Gleich G J. Induction of nasal late-phase reactions by insufflation ot' ragweed-pollen extract. J ALLERGY(?l,~t~ l,~,,~t!,~O!, t984:73: 363-8, 16, Kaliner M. Hypotheses on the contribution of late-phase Ntergic responses to the understanding and treatment of allergic diseases. J ALLERGYCUN IMMUNOL1984;73:31 I' I5. 17. Proctor DF, Adams GK III. Physiology ,and pharmacok,'gy of nasal function and mucus secretion Pharmac Ther [B] 1976;2:493-509. 18. Nitzan M, Brama I, Mahler Y, Measurement of nasal mucosal blood flow by a thermal clearance method IEEE T?ans Biomed Eng t985;32 t2:1063-66. 19. Kumlein J, Perbeck L. Fluourescein flowmetr~ in human nasal mucosa. Acta Otolaryngol 1986;101:286-9. 20. Abe Y, Jackson RT. The use of labeled micmspheres to determine blood flow in the dog's nasal mt~cos;~ Ann Otol 1972;8t:82-6. 21. Sejrsen P Blood flow in cutaneous tissue m man studied by washout of radioactive xenon. Circ Res 1969;25;215-29, 22, Aukland K, Bower BF, Berliner RW, Meast~rement of local blood flow with hydrogen gas. Circ Res 1964;14:164-87, 23. Stern MD, Lappe DL, Bowen PD, Chimosky ,lEo Hotloway GA Jr, Keiser HR, Bowman RL, Continuous, measurement of tissue blood flow by laser-Doppler spectroscopy. Am J Physiol 1977:232:H44t-8. 24. Olsson E Bende M, Ohlin P. The laser-Doppler ~lowmeter lot measuring microcirculation in human nasal mucosa, Acta Otolaryngol 1985;99:133-9. 25. Holmberg K, Bake B, Pipkorn U. Nasal mucosai blood flow after intranasal allergen challenge. J ALI,ER("~"CIIN IMMUNOL t988;81:54t-7, 26. Bende M, Elner A, Ohlin P. The effect of provoked allergic reaction and histamine on nasal mucosal blood flow in humans. Acta Ototaryngol 1984;97:99-104. 27. Juliusson S, Bende M. Allergic reaction of the human nasm mucosa studied with laser-Doppler flowme~. Clin Allergy 1987:17:301-5. 28. Olanoff LS, Titus CR, Sbea MS~ Gibson RE, Brooks CD. Effect of intranasal histamine on nasal muco~al bl~xqdflow and
508
29.
30. 31.
32.
33.
34.
35.
36. 37.
38.
Druce
J. ALLERGYCLIN, IMMUNOL MARCH 1988
the antidiuretic activity of desmopressin. J Clin Invest 1987;80:890-5. Bende M, Flisberg K, Larsson I, Ohlin P, Olsson P. A method for determination of blood flow with ~33Xe in human nasal mucosa. Acta Otolaryngol 1983;96:277-85. Cole E Halght JSJ. Posture and nasal patency. Am Rev Respir Dis 1984;129:351-4. Bende M. Blood flow with ~33Xein human nasal mucosa in relation to age, sex, and body position. Acta Otolaryngol 1983;96:175-9. Tanimoto H, Okuda M, Yagi T, Ohtsuka H. Measurement of the blood flow of the nasal mucosa by the hydrogen clearance method. Rhinology 1983;21:59-65. Druce HM, Bonner RF, Patow C, Choo P, Summers ILl, Kaliner MA. Response of nasal blood flow to neurohormones as measured by laser-Doppler velocimetry. J Appl Physiol 1984;57(4):1276-83. Bonner RF, Clem TR, Bowen PD, Bowman RL. LaserDoppler continuous real-time monitor of putsatile and mean blood flow in tissue microcircutation. In: Chen SH, Chu B, Nossal R, eds. Scattering techniques applied to supramolecular and nonequilibrium systems. New York: Plenum, 1981:685-702. Mellander S, Johansson B. Control of resistance, exchange, and capacitance functions in the peripheral circulation. Pharmacol Rev 1968;20: 117-96. Rothe CF. Reflex control of veins and vascular capacitance. Physiol Rev 1983;63:1281-1342. Intaglietta M. Vasomotor activity, time-dependent fluid exchange, and tissue pressure. Microvasc Res 1981;21:15364. Salathe EP, Venkataraman R, Gross JE Microcirculatory response to periodic pulsations in capillary pressure. Microvasc Res 1982;24:272-95.
39. Mygind N. Nasal allergy. 2rid ed. Oxford: Blackwell, chap 9, 1979:140-54. 40. Cole P. Modification of inspired air. In: Proctor DF, Andersen I, eds. The nose: upper airway physiology and the atmospheric environment. Amsterdam: Elsevier, 1982:351-75. 41. Engelhart M, Kristensen JK. Evaluation of cutaneous blood flow responses by 133Xewashout and a laser-Doppler flowmeter. J Invest Dermatol 1983;80:12-15. 42. Olsson P. A comparison between the 133Xewashout and laserDoppler techniques for estimation of nasal mucosal blood flow in humans. Acta Otolaryngol 1986;102:106-12. 43. Pleschka K, Sugahara M, Hashimoto M, Sommerlad V, Lurkens I, Ernst C. Local circulatory control in thermal stress. In: Dejours P, ed. Comparative physiology of environmental adaptations, vol 2. Eighth ESCP Conference, Strasbourg, 1986. Basel: S Karger AG, 1987:107-22. 44. Smits GJ, Roman RJ, Lombard JH. Evaluation of laserDoppler flowmetry as a measure of tissue blood flow. J Appl Physiol 1986;61(2):666-72. 45. Anggard A, Edwalt L. The effects of sympathetic nerve stimulation on the tracer disappearance rate and local blood content in the nasal mucosa of the cat. Acta Otolaryngol 1974;77: 131-9. 46. Andersson K-E, Bende M. Adrenoceptors in the control of human nasal mucosal blood flow. Ann Otol Rhinol Laryngol 1984;93:179-82. 47. Settipane GA. Allergic rhinitis update. Otolaryngol Head Neck Surg 1986;94:470-5. 48. Togias AG, Naclerio RM, Warner J, Proud D, Kagey-Sobotka A, Nimmagadda I, Norman PS, Lichtenstein LM. Demonstration of inhibition of mediator release from human mast cells by azatadine base. JAMA 1986;255:225-9. 49. Stoksted P. Rhinometric measurements for determination of the nasal cycle. Acta Otolaryngol 1953;109(suppl):159-75.
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