Ann 0101 84: 1975
EFFECT OF MICROAEROSOL INHALATION ON THE PATTERN OF BREATHING CLARENCE T. SASAKI, TADASHI AKITAYA,
M.D.
M.D.
ANDREW NEWMAN, JOHN
A.
KIRCHNER,
B.A. M.D.
NEW HAVEN, CONNECTICUT
SUMMARY - The nose and supraglottic larynx appear to play significant roles in the modification of the breathing pattern in response to a nonirritating solution delivered as a microaerosol. Slower breathing, reflexly produced by such a method, might benefit partial airway obstruction by reducing turbulence and, therefore, the work of breathing without altering tidal volume.
Stimulation of the upper respiratory crease or decrease of inspiratory time tract is known to cause reflex alterations and tidal volume. Such a variety of rein the pattern of breathing. Bert,' as sponses may be attributed to nonselecearly as 1867, reported such effects in tive electrical stimulation of a mixed rabbits produced by chloroform irrita- afferent nerve. Finally, Boushey'? tion of the nose and mouth. Kratschmer'' ( 1972), in a well-controlled study, ( 1870) demonstrated slowing of breath- quantitatively demonstrated that slower ing brought about by chemical, me- breathing with increased bronchoeonchanical, and thermal irritation of the striction occurred in cats through both nose. Beyer (1901) and Magne et al 4 mechanical and chemical irritation of ( 1925) confirmed respiratory inhibition the laryngeal mucosa. These responses, caused by irritant gases on the upper however, were abolished by denervarespiratory tract and also demonstrated tion of the larynx. in rabbits that this reflex inhibition Thus, investigators have come to reccould then be abolished by sectioning ognize that the nasal and laryngeal muthe trigeminal nerves. cosa are richly innervated and exFurther experimental evidence, how- quisitely sensitive to a variety of gross ever, seemed to indicate the larynx as mechanical and chemical stimuli,u-15 an additional source of such an inhib- The purpose of this study is to examine itory reflex, Franck" (1876) produced the role of the upper respiratory tract slowing of respiration by selective stim- and bronchi in the reflex modification of ulation of the larynx in rabbits with breathing under conditions of selective weak ammonia vapor. Other investi- microaerosol stimulation. Does saline gators.v" who electrically stimulated the microaerosol, while not itself chemically superior laryngeal nerve of cats and irritative. quantitatively alter the patdogs. obtained a variety of responses tern of breathing through stimulation which included expiratory apnea and of surface mucosal receptors? This inslowing of breathing with either in- vestigation hopes to explain, in part, the From the Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut. Supported by USPHS 2-ROl-NS-05465-08 Presented at the Committee for Research Meeting of the A.A.O.O. in Dallas, Texas, October 5, 1974. 344
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345
MICROAEROSOL AND BREATHING
clinical effects of mist inhalation as an accepted form of treatment, for example, in the initial management of subglottic croup and other forms of partial upper airway obstruction. The mechanism of the patient's favorable response to this time-tested remedy has not been generally understood.
aerosol administration. The tracheotomy was then closed and an oral tube introduced above the epiglottis to allow direct aerosol stimulation of the larynx in the spontaneously breathing cat. Phrenic activity was again compared before and after aerosol application. The supraglottic larynx was then denervated by bilateral superior laryngeal nerve section or topically anesthesized with 1 % tetracaine hydrochloride. Phrenic recordings were repeated.
METHODS AND MATERIALS
Nasal breathing was subsequently induced by simple mouth closure, allowing selective nasal stimulation with microaerosol administered through a face mask. Phrenic signals were again compared before and after the stimulus. The effects of simultaneous laryngeal and nasal anesthesia were finally observed in the nose-breathing cat (larynx anesthetized) by topical anesthesia of the nasal mucous membranes as well with 1 % tetracaine hydrochloride solution.
Ten adult cats, weighing 2.5 to 4.0 kg each, were used. Anesthesia was induced intraperitoneally with pentobarbital sodium, 30-35 mg/kg body weight. In order to maintain a uniform degree of anesthesia, the right femoral vein was cannulated to allow pentobarbital administration at necessary intervals to abolish the lid reflex. Thus, a uniform depth of anesthesia seemed to ensure a uniform breathing rate, facilitating the comparison of test results among the ten cats. Through a midline vertical neck incision, the C. motor contribution to the right phrenic nerve was identified within the scalene fascia. The nerve was transected low in the neck, stripped of its epineurium, and prepared in a mineral oil bath. A bipolar platinum electrode was used to record multifiber activity from the cut end of the central stump. The phrenic signal was then amplified by a preamplifier" and an amplifier.... for display by a pen oscillograph. ...... In addition, this basic signal was electronically rectified and integrated by the integrator section and displayed simultaneously on a second oscillographic channel. Cardiac pulse rate was monitored from a concentric needle electrode embedded in the skin of the anterior chest. This electrocardiogram was also displayed on the oscillograph. Arterial blood gas analysis was performed from the right femoral artery using an acid-base analyzert and microelectrode unit. A nebulizert was used to produce a saline aerosol consisting of particles 1-8 Il. in diameter. This aerosol was delivered at room temperature, 74F. Three test situations were considered in spontaneously breathing cats: 1) selective tracheobronchial stimulation, 2) selective laryngeal stimulation, and 3) selective nasal stimulation. The following test protocol was used in each cat. A tracheotomy was initially performed and a tracheal cannula temporarily inserted for the direct administration of saline microaerosol to the tracheobronchial tree. Phrenic activity was measured before and after
Phrenic discharge function was evaluated by the following parameters: breathing rate, time of inspiration (t insp.), time of expiration (t exp.), phrenic peak, and phrenic slope. Measurements were made from the basic phrenic discharge patterns (ENG) and from their integrated functions. Breathing rate was defined as the number of inspiratory bursts per minute. T Insp. was measured in seconds from the beginning of the inspiratory burst to the end of the diphasic electrical activity. T expo was measured from the end of the inspiratory burst to the heginning of the next. Phrenic peak represented the maximum amplitude of the integrated phrenic function. Phrenic slope was the ratio of one-half the phrenic peak to the elapsed time interval from the beginning of integrated activity. An average measurement for each test situation during a given trial was computed from three consecutive breaths. Corresponding average measurements obtained in this way for each test situation were then averaged with respect to ten trials in seven cats. Since absolute values of phrenic measurements varied with the arbitrary setting of the electronic integrator, stimulus response was expressed as percent change with respect to control values. The significance of these changes were calculated with respect to controls using the students' t test for paired, comparison analysis. RESULTS
Seven cats (ten trials) were ultimately used for computation of the following results. Three of the original
.. 7P3, Grass Instrument, Quincy, Massachusetts .... 7DA, Grass Instrument, Quincy, Massachusetts ...... Model 7 Polygraph, Grass Instrument, Quincy, Massachusetts t PHM 71, Radiometer, Copenhagen, Denmark :j: Mistogen Equipment Co., Oakland, California
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346
SASAKI ET AL. TABLE I
RESPONSES OF TRACHEOBRONCHIAL, LARYNGEAL, AND NASAL STIMULATION
Cats Trials
Rate
Slope
Tinsp.
Texp.
+0.4 ± 1.1
+0.7 ± 0.3
Tracheobronchial Stimulation Laryngeal Stimulation
7
10
+0.8 ± 0.6
-1.1 ± 0.9
7
10
-18.5 ± 1.5 -34.9 ± 3.7
......
.. ....
+20.5 ± 2.0 +31.7 ± 1.4
.. ....
.. ....
Laryngeal Stimulation ( larynx anesthetized) Nasal Stimulation
7
10
+0.1 ± 0.3
+0.1 ± 0.8
-0.5 ± 0.3
+0.1 ± 0.2
7
10
-21.6 ± 1.1 -53.0 ± 1.8 +23.4 ± 2.5 +30.7 ±2.0
......
.. ....
.. ....
.. ....
Nasal Stimulation ( larynx and nose anesthetized)
7
10
+0.3 ± 0.3
-2.1 ± 1.9
-0.3 ± 1.0
-0.1 ± 0.5
Values represent mean % change and standard error "p < .05, .... p < .01, ......p < .001 for comparison of mean % change against mean control.
ten cats had been eliminated from the study, one suffering anesthetic death and two presenting technical difficulty in phrenic nerve preparation. No discernible change in the pattern of breathing was effected by the administration of saline microaerosol through the tracheal cannula (tracheobronchial stimulation) (Fig. 1, Table I). The pulse rate and blood gases remained unaltered.
A
a ...
..
..
B
a •
--Ssec Fig. 1. Tracheobronchial stimulation: A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity a) during microaerosol stimulation. phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
Laryngeal stimulation with saline microaerosol produced significant slowing of the inspiratory effort (Fig. 2, Table I). The average breathing rate decreased by 18.5% with corresponding increases of t insp, by 20.5% and t expo by 31.7%. The phrenic slope decreased by 34.9% while pulse rate and blood gases remained unchanged. This reflex was essentially abolished by either bilateral superior laryngeal nerve section or tropical anesthesia of the lamyx (Fig. 3, Table I). Selective nasal stimulation in the spontaneously breathing cat was possible after laryngeal anesthesia. Microaerosol stimulation of the nose also caused slowing of inspiration (Fig. 4, Table I). The average breathing rate decreased by 21.6% with corresponding increases in t insp. by 23.4% and t expo by 30.7%. In contrast to responses from laryngeal stimulation, nasal stimulation produced marked decrease in phrenic slope by 53.0%. Pulse rate and blood gases remained unchanged. This reflex was abolished by topical anesthesia of the nasal mucous membranes, (Fig. 5, Table I). Phrenic peak did not change significantly from one test situation to another. Coughing or sneezing did not occur at any time in response to the stimulus. COMMENT
Microaerosol stimulation of the nose
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MICROAEROSOL AND BREATHING
A
B
a
1••'
••
••
I
b
--5sec Fig. 2. Laryngeal stimulation: A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
A
B
allltlt 4It '-Ii.
I'" ..
--5sec Fig. 3. Laryngeal stimulation after bilateral superior laryngeal nerve section: A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
347
and larynx consistently results in slowing of the inspiratory effort. This is in contrast to tracheobronchial stimulation which results in no discernible respiratory response. Clearly, nasal and laryngeal anesthesia abolishes the afferent limb of this reflex. In this regard the role of the trigeminal and superior laryngeal nerves is obvious. Superior laryngeal nerve section, in fact, completely abolishes this reflex response when the larynx is selectively stimulated. Since the superior laryngeal nerves largely innervate the supraglottic larynx, it appears that this portion of the larynx is critical to the observed respiratory responses. The glossopharyngeal nerve does not appear to participate significantly in the described responses since nasal and laryngeal anesthesia alone completely abolishes the observed reflex. It is interesting to note, however, that Biscoe and Sampson16 ' 18 have described transient inhibition of phrenic activity with single shock stimulation of the IX cranial nerve. The role of pulmonary vagal afferents in the mediation of the observed responses requires discussion. A change in phrenic slope indicates a direct central response of the nose and larynx to the aerosol stimulus, independent of vagal afferent influences. The argument against pulmonary vagal influences is three-fold: 1) Direct tracheobronchial stimulation with aerosol produces no measurable respiratory effect; 2) While certain vagal reflexes may alter the duration of inspiration1 9 ' 21 • the vagus does not itself centrally influence the rate of phrenic discharge build up ( phrenic slope) ;6.22.24 and 3) Because the vagi are largely inhibitory in nature, vagotomy releases the medullary respiratory center from peripheral inhibition resulting in noticeable reflex hyperpnea. Thus, vagotomy may alter the resting pattern of breathing, but it does not appear to alter observed respiratory responses to laryngeal stimulation. Boushey et alto have confirmed this observation in vagotomized cats. Clearly, therefore, pulmonary vagal influence
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348
SASAKI ET AL.
does not appear to be involved in the observed experimental responses.
A
b B
li.i.
a
b
--Ssec Fig. 4. Nasal stimulation (superior laryngeal nerves sectioned): A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic eIectroneurogram. b) integrated function of phrenic nerve discharge.
A
In order to minimize technical variables, ventilatory measurements were not attempted in this study. Nevertheless, certain measurements of phrenic electrical activity may be correlated with standard ventilatory values. Based upon the work of Huszczuk and Widdecomb;" 1973, the peak of the integrated phrenic discharge correlates directly with tidal volume. Similarly, a direct correlation may be made between phrenic slope and tracheal air How, based upon work by Nail et al,26 1972. From these correlations it is therefore possible to assume the following ventilatory information. Microaerosol stimulation of the unanesthetized nose and larynx produces slowing of breathing. Furthermore, while tidal volume (phrenic peak) remains unchanged, air How (phrenic slope) decreases, resulting in less turbulence for a given tidal volume. The possible benefits of such ventilatory dynamics in a constricted airway may be appreciated. SUMMARY
aa., b,..
B ~ a'''.'ll''''''''
4. . . . . . . .
• •
..,·· • •
,. .... ".
a
•
,
--5sec Fig. 5. Nasal stimulation after intranasal topical anesthesia (superior laryngeal nerves sectioned): A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
Microaerosol stimulation of the trachea and bronchi appears to have no effect on the pattern of breathing. However, laryngeal stimulation with microaerosol produces consistent changes characterized by slowing of the inspiratory effort. The reHex response can be abolished by either bilateral superior laryngeal nerve section or topical anesthesia of the laryngeal mucous membranes. Nasal stimulation with saline microaerosol results in marked slowing of inspiration. This response can also be blocked by topical anesthesia of the nasal mucosa. The decreased breathing rate results from both increased t insp. and t expo During inspiration the buildup phrenic discharge activity, the phrenic slope, decreases. The phrenic peak, however, remains unchanged. The nose and larynx, therefore, appear to play significant roles in the modification of the breathing pattern in
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MICROAEROSOL AND BREATHING
response to a nonirritating solution delivered as a microaerosol. Slower breathing, reflexly produced in the human being by such a method, might benefit partial airway obstruction by
349
reducing turbulence and therefore the work of breathing. It is speculated that in a marginally competent upper airway, this benefit might be a critical factor in survival.
333 CEDAR ST., NEW HAVEN, CONN. 06510. REFERENCES
1. Bert MP: Sur 1a pretendue period d'excitation de l'empoisonment des animaux par Ie chloroforme ou par l'ether. C. R. Hebd SeanC Acad Sci, Paris, 64:622-625, 1867 2. Kratschmer F: Uber Reflexe von der Nasenschleimhaut auf Athmung und Kreislauf. Wiener Akademie der Wissenschaften Math. Naturw Klasse Sitzungsberichte 62:147-170, 1870 3. Beyer H: Athem-reflexe auf Olfactoriusreiz, Arch Anat Physiol (Suppl) 261-275, 1901 4. Magne H, Mayer A, Plantefol L: Recherches sur les actions reflexes produites par l'irritation des voies respiratoires. Ann Physiol Physicochim Bioi 1:394-427, 1925 5. Franck MF: Recherches experimentales sur les effets cardiaques, vasculaires, et respiratoires des excitations douloureuses. C. R. Hebd. Acad Sci, Paris 83:1109-1111, 1876 6. Larrabee MG, Hodes R: Cyclic changes in the respiratory centers, revealed by the effects of afferent impulses. Am J Physiol155: 147-178, 1948 7. Aldaya F: Les modifications reflexes de la respiration par l'excitation du nerf larynge superieur. C. R. SeanC, Soc BioI 123: 104105, 1936 8. Hammouda M, Wilson WH: Reflex acceleration of respiration arising from excitation of the vagus or its terminations in the lung. J PhysioI94:497-524, 1939 9. Gesell R, Hamilton MA: Reflexogenic components of breathing. Am J Physiol 133: 694-719, 1941 10. Boushey HA, Richardson PS, Widdecombe JG: Reflex effects of laryngeal irritation on the pattern of breathing and total lung resistance. J Physiol 224:501-513, 1972 II. Angell-james JE, Daley MdeB: Nasal reflexes. Proc R Soc Med 62:1287-1293, 1969 12. Angell-james JE, Daley MdeB: Reflex respiratory and cariovascular effects of stimulation of receptors in the nose of the dog. J Physiol 220: 673-696, 1972 13. Nadel JA, Widdecombe JG: Reflex effects of upper airway irritation on total lung resistance and blood pressure. J Appl Physiol 17:861-865,1962 14. Tomori Z, [avorka K, Stransky A: Cardiovascular, respiratory, and glottal changes
during the apneic reflex of olfactory-trigeminal and vagal origin. Physiol Bohemoslov 21:4552, 1972 15. Szereda-Przestaszewska M, Widdecombe JG: Reflex effects of chemical irritation of the upper airways on the laryngeal lumen in cats. Respir PhysioI18:107-115, 1973 16. Biscoe TJ, Sampson SR: Field potentials evoked in the brain stem of the cat bv stimulation of the carotid sinus, glossopharyngeal, aortic, and superior laryngeal nerves. J Physiol 209:341-358, 1970 17. Biscoe TJ, Sampson SR: Responses of cells in the brain stem of the cat by stimulation of the sinus, glossopharyngeal, aortic, and superior laryngeal nerves. J Physiol 209:359373, 1970 18. Biscoe TJ, Sampson SR: An analysis of the inhibition of phrenic motoneurones which occurs on stimulation of some cranial nerve afferents. J Physiol 209:375-393, 1970 19. Breuer J: Die Selbststeuerung der Athmung durch den Nervus Vagus. Wiener Akademie der Wissenschaften Math. Naturw Klasse Sitzungsberichte 58:909-937, 1868 20. Hering E: Die Selbststeuerung der Athmung durch den Nervus Vagus. Wiener Akademie der Wissenschaften Math. Naturw. Klasse Sitzungsberichte 57:672-677, 1868 21. Head H: On the regulation of respiration. J Physiol 10: 1-70, 1889 22. Boyd TE, Maaske CA: Vagal inhibition of inspiration and accompanying changes of respiratory rhythm. J Neurophysiol 2:533542, 1939 23. Larrabe MG, Knowlton GC: Excitation and inhibition of phrenic motoneurones by inflation of the lungs. Am J .Physiol 147 :90-99 1946 ' 24. Clark FJ, Euler C von: On the regulation of depth and rate of breathing. J Physiol 222:267-295, 1972 25. Huszczuk A, Widdecombe JG: Studies on central repiratory activity in artificially ventilated rabbits. Acta Neurobiol Exp (Warsz ) 33:391-400, 1973 26. Nail BS, Sterling GM, Widdecombe JG: Patterns of spontaneous and reflexly-induced activity in phrenic and intercostal motoneurones. Exp Brain Res 15:318-332 1972 '
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EFFECT OF MICROAEROSOL INHALATION ON THE PATTERN OF BREATHING CLARENCE T. SASAKI, TADASHI AKITAYA,
M.D.
M.D.
ANDREW NEWMAN, JOHN
A.
KIRCHNER,
B.A. M.D.
NEW HAVEN, CONNECTICUT
SUMMARY - The nose and supraglottic larynx appear to play significant roles in the modification of the breathing pattern in response to a nonirritating solution delivered as a microaerosol. Slower breathing, reflexly produced by such a method, might benefit partial airway obstruction by reducing turbulence and, therefore, the work of breathing without altering tidal volume.
Stimulation of the upper respiratory crease or decrease of inspiratory time tract is known to cause reflex alterations and tidal volume. Such a variety of rein the pattern of breathing. Bert,' as sponses may be attributed to nonselecearly as 1867, reported such effects in tive electrical stimulation of a mixed rabbits produced by chloroform irrita- afferent nerve. Finally, Boushey'? tion of the nose and mouth. Kratschmer'' ( 1972), in a well-controlled study, ( 1870) demonstrated slowing of breath- quantitatively demonstrated that slower ing brought about by chemical, me- breathing with increased bronchoeonchanical, and thermal irritation of the striction occurred in cats through both nose. Beyer (1901) and Magne et al 4 mechanical and chemical irritation of ( 1925) confirmed respiratory inhibition the laryngeal mucosa. These responses, caused by irritant gases on the upper however, were abolished by denervarespiratory tract and also demonstrated tion of the larynx. in rabbits that this reflex inhibition Thus, investigators have come to reccould then be abolished by sectioning ognize that the nasal and laryngeal muthe trigeminal nerves. cosa are richly innervated and exFurther experimental evidence, how- quisitely sensitive to a variety of gross ever, seemed to indicate the larynx as mechanical and chemical stimuli,u-15 an additional source of such an inhib- The purpose of this study is to examine itory reflex, Franck" (1876) produced the role of the upper respiratory tract slowing of respiration by selective stim- and bronchi in the reflex modification of ulation of the larynx in rabbits with breathing under conditions of selective weak ammonia vapor. Other investi- microaerosol stimulation. Does saline gators.v" who electrically stimulated the microaerosol, while not itself chemically superior laryngeal nerve of cats and irritative. quantitatively alter the patdogs. obtained a variety of responses tern of breathing through stimulation which included expiratory apnea and of surface mucosal receptors? This inslowing of breathing with either in- vestigation hopes to explain, in part, the From the Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut. Supported by USPHS 2-ROl-NS-05465-08 Presented at the Committee for Research Meeting of the A.A.O.O. in Dallas, Texas, October 5, 1974. 344
Downloaded from aor.sagepub.com at Harvard Libraries on July 7, 2015
345
MICROAEROSOL AND BREATHING
clinical effects of mist inhalation as an accepted form of treatment, for example, in the initial management of subglottic croup and other forms of partial upper airway obstruction. The mechanism of the patient's favorable response to this time-tested remedy has not been generally understood.
aerosol administration. The tracheotomy was then closed and an oral tube introduced above the epiglottis to allow direct aerosol stimulation of the larynx in the spontaneously breathing cat. Phrenic activity was again compared before and after aerosol application. The supraglottic larynx was then denervated by bilateral superior laryngeal nerve section or topically anesthesized with 1 % tetracaine hydrochloride. Phrenic recordings were repeated.
METHODS AND MATERIALS
Nasal breathing was subsequently induced by simple mouth closure, allowing selective nasal stimulation with microaerosol administered through a face mask. Phrenic signals were again compared before and after the stimulus. The effects of simultaneous laryngeal and nasal anesthesia were finally observed in the nose-breathing cat (larynx anesthetized) by topical anesthesia of the nasal mucous membranes as well with 1 % tetracaine hydrochloride solution.
Ten adult cats, weighing 2.5 to 4.0 kg each, were used. Anesthesia was induced intraperitoneally with pentobarbital sodium, 30-35 mg/kg body weight. In order to maintain a uniform degree of anesthesia, the right femoral vein was cannulated to allow pentobarbital administration at necessary intervals to abolish the lid reflex. Thus, a uniform depth of anesthesia seemed to ensure a uniform breathing rate, facilitating the comparison of test results among the ten cats. Through a midline vertical neck incision, the C. motor contribution to the right phrenic nerve was identified within the scalene fascia. The nerve was transected low in the neck, stripped of its epineurium, and prepared in a mineral oil bath. A bipolar platinum electrode was used to record multifiber activity from the cut end of the central stump. The phrenic signal was then amplified by a preamplifier" and an amplifier.... for display by a pen oscillograph. ...... In addition, this basic signal was electronically rectified and integrated by the integrator section and displayed simultaneously on a second oscillographic channel. Cardiac pulse rate was monitored from a concentric needle electrode embedded in the skin of the anterior chest. This electrocardiogram was also displayed on the oscillograph. Arterial blood gas analysis was performed from the right femoral artery using an acid-base analyzert and microelectrode unit. A nebulizert was used to produce a saline aerosol consisting of particles 1-8 Il. in diameter. This aerosol was delivered at room temperature, 74F. Three test situations were considered in spontaneously breathing cats: 1) selective tracheobronchial stimulation, 2) selective laryngeal stimulation, and 3) selective nasal stimulation. The following test protocol was used in each cat. A tracheotomy was initially performed and a tracheal cannula temporarily inserted for the direct administration of saline microaerosol to the tracheobronchial tree. Phrenic activity was measured before and after
Phrenic discharge function was evaluated by the following parameters: breathing rate, time of inspiration (t insp.), time of expiration (t exp.), phrenic peak, and phrenic slope. Measurements were made from the basic phrenic discharge patterns (ENG) and from their integrated functions. Breathing rate was defined as the number of inspiratory bursts per minute. T Insp. was measured in seconds from the beginning of the inspiratory burst to the end of the diphasic electrical activity. T expo was measured from the end of the inspiratory burst to the heginning of the next. Phrenic peak represented the maximum amplitude of the integrated phrenic function. Phrenic slope was the ratio of one-half the phrenic peak to the elapsed time interval from the beginning of integrated activity. An average measurement for each test situation during a given trial was computed from three consecutive breaths. Corresponding average measurements obtained in this way for each test situation were then averaged with respect to ten trials in seven cats. Since absolute values of phrenic measurements varied with the arbitrary setting of the electronic integrator, stimulus response was expressed as percent change with respect to control values. The significance of these changes were calculated with respect to controls using the students' t test for paired, comparison analysis. RESULTS
Seven cats (ten trials) were ultimately used for computation of the following results. Three of the original
.. 7P3, Grass Instrument, Quincy, Massachusetts .... 7DA, Grass Instrument, Quincy, Massachusetts ...... Model 7 Polygraph, Grass Instrument, Quincy, Massachusetts t PHM 71, Radiometer, Copenhagen, Denmark :j: Mistogen Equipment Co., Oakland, California
Downloaded from aor.sagepub.com at Harvard Libraries on July 7, 2015
346
SASAKI ET AL. TABLE I
RESPONSES OF TRACHEOBRONCHIAL, LARYNGEAL, AND NASAL STIMULATION
Cats Trials
Rate
Slope
Tinsp.
Texp.
+0.4 ± 1.1
+0.7 ± 0.3
Tracheobronchial Stimulation Laryngeal Stimulation
7
10
+0.8 ± 0.6
-1.1 ± 0.9
7
10
-18.5 ± 1.5 -34.9 ± 3.7
......
.. ....
+20.5 ± 2.0 +31.7 ± 1.4
.. ....
.. ....
Laryngeal Stimulation ( larynx anesthetized) Nasal Stimulation
7
10
+0.1 ± 0.3
+0.1 ± 0.8
-0.5 ± 0.3
+0.1 ± 0.2
7
10
-21.6 ± 1.1 -53.0 ± 1.8 +23.4 ± 2.5 +30.7 ±2.0
......
.. ....
.. ....
.. ....
Nasal Stimulation ( larynx and nose anesthetized)
7
10
+0.3 ± 0.3
-2.1 ± 1.9
-0.3 ± 1.0
-0.1 ± 0.5
Values represent mean % change and standard error "p < .05, .... p < .01, ......p < .001 for comparison of mean % change against mean control.
ten cats had been eliminated from the study, one suffering anesthetic death and two presenting technical difficulty in phrenic nerve preparation. No discernible change in the pattern of breathing was effected by the administration of saline microaerosol through the tracheal cannula (tracheobronchial stimulation) (Fig. 1, Table I). The pulse rate and blood gases remained unaltered.
A
a ...
..
..
B
a •
--Ssec Fig. 1. Tracheobronchial stimulation: A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity a) during microaerosol stimulation. phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
Laryngeal stimulation with saline microaerosol produced significant slowing of the inspiratory effort (Fig. 2, Table I). The average breathing rate decreased by 18.5% with corresponding increases of t insp, by 20.5% and t expo by 31.7%. The phrenic slope decreased by 34.9% while pulse rate and blood gases remained unchanged. This reflex was essentially abolished by either bilateral superior laryngeal nerve section or tropical anesthesia of the lamyx (Fig. 3, Table I). Selective nasal stimulation in the spontaneously breathing cat was possible after laryngeal anesthesia. Microaerosol stimulation of the nose also caused slowing of inspiration (Fig. 4, Table I). The average breathing rate decreased by 21.6% with corresponding increases in t insp. by 23.4% and t expo by 30.7%. In contrast to responses from laryngeal stimulation, nasal stimulation produced marked decrease in phrenic slope by 53.0%. Pulse rate and blood gases remained unchanged. This reflex was abolished by topical anesthesia of the nasal mucous membranes, (Fig. 5, Table I). Phrenic peak did not change significantly from one test situation to another. Coughing or sneezing did not occur at any time in response to the stimulus. COMMENT
Microaerosol stimulation of the nose
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MICROAEROSOL AND BREATHING
A
B
a
1••'
••
••
I
b
--5sec Fig. 2. Laryngeal stimulation: A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
A
B
allltlt 4It '-Ii.
I'" ..
--5sec Fig. 3. Laryngeal stimulation after bilateral superior laryngeal nerve section: A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
347
and larynx consistently results in slowing of the inspiratory effort. This is in contrast to tracheobronchial stimulation which results in no discernible respiratory response. Clearly, nasal and laryngeal anesthesia abolishes the afferent limb of this reflex. In this regard the role of the trigeminal and superior laryngeal nerves is obvious. Superior laryngeal nerve section, in fact, completely abolishes this reflex response when the larynx is selectively stimulated. Since the superior laryngeal nerves largely innervate the supraglottic larynx, it appears that this portion of the larynx is critical to the observed respiratory responses. The glossopharyngeal nerve does not appear to participate significantly in the described responses since nasal and laryngeal anesthesia alone completely abolishes the observed reflex. It is interesting to note, however, that Biscoe and Sampson16 ' 18 have described transient inhibition of phrenic activity with single shock stimulation of the IX cranial nerve. The role of pulmonary vagal afferents in the mediation of the observed responses requires discussion. A change in phrenic slope indicates a direct central response of the nose and larynx to the aerosol stimulus, independent of vagal afferent influences. The argument against pulmonary vagal influences is three-fold: 1) Direct tracheobronchial stimulation with aerosol produces no measurable respiratory effect; 2) While certain vagal reflexes may alter the duration of inspiration1 9 ' 21 • the vagus does not itself centrally influence the rate of phrenic discharge build up ( phrenic slope) ;6.22.24 and 3) Because the vagi are largely inhibitory in nature, vagotomy releases the medullary respiratory center from peripheral inhibition resulting in noticeable reflex hyperpnea. Thus, vagotomy may alter the resting pattern of breathing, but it does not appear to alter observed respiratory responses to laryngeal stimulation. Boushey et alto have confirmed this observation in vagotomized cats. Clearly, therefore, pulmonary vagal influence
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348
SASAKI ET AL.
does not appear to be involved in the observed experimental responses.
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--Ssec Fig. 4. Nasal stimulation (superior laryngeal nerves sectioned): A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic eIectroneurogram. b) integrated function of phrenic nerve discharge.
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In order to minimize technical variables, ventilatory measurements were not attempted in this study. Nevertheless, certain measurements of phrenic electrical activity may be correlated with standard ventilatory values. Based upon the work of Huszczuk and Widdecomb;" 1973, the peak of the integrated phrenic discharge correlates directly with tidal volume. Similarly, a direct correlation may be made between phrenic slope and tracheal air How, based upon work by Nail et al,26 1972. From these correlations it is therefore possible to assume the following ventilatory information. Microaerosol stimulation of the unanesthetized nose and larynx produces slowing of breathing. Furthermore, while tidal volume (phrenic peak) remains unchanged, air How (phrenic slope) decreases, resulting in less turbulence for a given tidal volume. The possible benefits of such ventilatory dynamics in a constricted airway may be appreciated. SUMMARY
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--5sec Fig. 5. Nasal stimulation after intranasal topical anesthesia (superior laryngeal nerves sectioned): A) Phrenic discharge pattern before microaerosol stimulation. B) Phrenic activity during microaerosol stimulation. a) phrenic electroneurogram. b) integrated function of phrenic nerve discharge.
Microaerosol stimulation of the trachea and bronchi appears to have no effect on the pattern of breathing. However, laryngeal stimulation with microaerosol produces consistent changes characterized by slowing of the inspiratory effort. The reHex response can be abolished by either bilateral superior laryngeal nerve section or topical anesthesia of the laryngeal mucous membranes. Nasal stimulation with saline microaerosol results in marked slowing of inspiration. This response can also be blocked by topical anesthesia of the nasal mucosa. The decreased breathing rate results from both increased t insp. and t expo During inspiration the buildup phrenic discharge activity, the phrenic slope, decreases. The phrenic peak, however, remains unchanged. The nose and larynx, therefore, appear to play significant roles in the modification of the breathing pattern in
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MICROAEROSOL AND BREATHING
response to a nonirritating solution delivered as a microaerosol. Slower breathing, reflexly produced in the human being by such a method, might benefit partial airway obstruction by
349
reducing turbulence and therefore the work of breathing. It is speculated that in a marginally competent upper airway, this benefit might be a critical factor in survival.
333 CEDAR ST., NEW HAVEN, CONN. 06510. REFERENCES
1. Bert MP: Sur 1a pretendue period d'excitation de l'empoisonment des animaux par Ie chloroforme ou par l'ether. C. R. Hebd SeanC Acad Sci, Paris, 64:622-625, 1867 2. Kratschmer F: Uber Reflexe von der Nasenschleimhaut auf Athmung und Kreislauf. Wiener Akademie der Wissenschaften Math. Naturw Klasse Sitzungsberichte 62:147-170, 1870 3. Beyer H: Athem-reflexe auf Olfactoriusreiz, Arch Anat Physiol (Suppl) 261-275, 1901 4. Magne H, Mayer A, Plantefol L: Recherches sur les actions reflexes produites par l'irritation des voies respiratoires. Ann Physiol Physicochim Bioi 1:394-427, 1925 5. Franck MF: Recherches experimentales sur les effets cardiaques, vasculaires, et respiratoires des excitations douloureuses. C. R. Hebd. Acad Sci, Paris 83:1109-1111, 1876 6. Larrabee MG, Hodes R: Cyclic changes in the respiratory centers, revealed by the effects of afferent impulses. Am J Physiol155: 147-178, 1948 7. Aldaya F: Les modifications reflexes de la respiration par l'excitation du nerf larynge superieur. C. R. SeanC, Soc BioI 123: 104105, 1936 8. Hammouda M, Wilson WH: Reflex acceleration of respiration arising from excitation of the vagus or its terminations in the lung. J PhysioI94:497-524, 1939 9. Gesell R, Hamilton MA: Reflexogenic components of breathing. Am J Physiol 133: 694-719, 1941 10. Boushey HA, Richardson PS, Widdecombe JG: Reflex effects of laryngeal irritation on the pattern of breathing and total lung resistance. J Physiol 224:501-513, 1972 II. Angell-james JE, Daley MdeB: Nasal reflexes. Proc R Soc Med 62:1287-1293, 1969 12. Angell-james JE, Daley MdeB: Reflex respiratory and cariovascular effects of stimulation of receptors in the nose of the dog. J Physiol 220: 673-696, 1972 13. Nadel JA, Widdecombe JG: Reflex effects of upper airway irritation on total lung resistance and blood pressure. J Appl Physiol 17:861-865,1962 14. Tomori Z, [avorka K, Stransky A: Cardiovascular, respiratory, and glottal changes
during the apneic reflex of olfactory-trigeminal and vagal origin. Physiol Bohemoslov 21:4552, 1972 15. Szereda-Przestaszewska M, Widdecombe JG: Reflex effects of chemical irritation of the upper airways on the laryngeal lumen in cats. Respir PhysioI18:107-115, 1973 16. Biscoe TJ, Sampson SR: Field potentials evoked in the brain stem of the cat bv stimulation of the carotid sinus, glossopharyngeal, aortic, and superior laryngeal nerves. J Physiol 209:341-358, 1970 17. Biscoe TJ, Sampson SR: Responses of cells in the brain stem of the cat by stimulation of the sinus, glossopharyngeal, aortic, and superior laryngeal nerves. J Physiol 209:359373, 1970 18. Biscoe TJ, Sampson SR: An analysis of the inhibition of phrenic motoneurones which occurs on stimulation of some cranial nerve afferents. J Physiol 209:375-393, 1970 19. Breuer J: Die Selbststeuerung der Athmung durch den Nervus Vagus. Wiener Akademie der Wissenschaften Math. Naturw Klasse Sitzungsberichte 58:909-937, 1868 20. Hering E: Die Selbststeuerung der Athmung durch den Nervus Vagus. Wiener Akademie der Wissenschaften Math. Naturw. Klasse Sitzungsberichte 57:672-677, 1868 21. Head H: On the regulation of respiration. J Physiol 10: 1-70, 1889 22. Boyd TE, Maaske CA: Vagal inhibition of inspiration and accompanying changes of respiratory rhythm. J Neurophysiol 2:533542, 1939 23. Larrabe MG, Knowlton GC: Excitation and inhibition of phrenic motoneurones by inflation of the lungs. Am J .Physiol 147 :90-99 1946 ' 24. Clark FJ, Euler C von: On the regulation of depth and rate of breathing. J Physiol 222:267-295, 1972 25. Huszczuk A, Widdecombe JG: Studies on central repiratory activity in artificially ventilated rabbits. Acta Neurobiol Exp (Warsz ) 33:391-400, 1973 26. Nail BS, Sterling GM, Widdecombe JG: Patterns of spontaneous and reflexly-induced activity in phrenic and intercostal motoneurones. Exp Brain Res 15:318-332 1972 '
Downloaded from aor.sagepub.com at Harvard Libraries on July 7, 2015
