Laryngeal narrowing during nasal ventilation does not originate from bronchopulmonary c-fibers

Contents lists available at Respiratory Physiology & Neurobiology Short communication Laryngeal narrowing during nasal ventilation does not originate from Nathalie Samson, Lalah Niane, Stéphanie Nault, Charlène Nadeau, Jean-Paul Praud Neonatal Respiratory Research Unit, Departments of Pediatrics and Physiology, Université de Sherbrooke, QC, Canada J1H 5N4 We previously showed that nasal pressure support ventilation (nPSV) can lead to active inspiratory laryn- Accepted 22 July 2014 geal narrowing, which originates from the stimulation of bronchopulmonary receptors. Among the three Available online 27 July 2014 major types of bronchopulmonary receptors, which are variably stimulated by lung distension, C-fiber endings are remarkable, given that their stimulation can also trigger laryngeal closure. Taking advantage of our lamb model with blocked C-fibers, we aimed to assess whether bronchopulmonary C-fiber end- ings are involved in the active inspiratory laryngeal narrowing during nPSV. Nine lambs were surgically Nasal pressure support ventilation instrumented to assess states of alertness, electrical activity of a glottal constrictor (EaTA), respiratory Thyroarytenoid muscle movements and arterial blood gases. Forty-eight hours later, two polysomnographic recordings were performed during nPSV 15/4 cmH2O, before and after C-fiber blockade. During nPSV, blockade of C-fibers did not prevent inspiratory EaTA (present for 74 ± 41% of respiratory cycles vs. 64 ± 35%, p = 0.9). We con- clude that active inspiratory laryngeal narrowing during nPSV does not originate from bronchopulmonary C-fiber endings.
2014 Published by Elsevier B.V.
normal breathing in some species. RAR stimulation provides a pos- itive feed-back to inspiratory drive, which is deemed responsible Over the past few years, we have documented that nasal for the occurrence of augmented breaths. Pulmonary CFEs are stim- pressure support ventilation (nPSV) induces an active laryngeal ulated by large lung distension. i.e., at least 1 tidal volume above narrowing during inspiration in non-sedated lambs ( residual capacity. In addition, CFE stimulation can lead Bussière This inspiratory laryngeal to active laryngeal closure, including in lambs narrowing can have deleterious consequences, including limitation which is of high relevance for our studies. From these premises, of lung ventilation as well as diversion of the overall aim of our ongoing investigations is to uncover the bron- the insufflated gas into the esophagus. We further showed that this chopulmonary receptor type(s) involved in the active, inspiratory inspiratory laryngeal narrowing during nPSV was reflexively driven laryngeal narrowing observed during nPSV. The specific aim of the by the stimulation of unidentified bronchopulmonary receptors present study was twofold: (i) to take advantage of our unique new- born lamb model with blocked CFEs in order Vagal afferent messages from the lungs originate from three to assess whether CFEs are involved; (ii) to perform exploratory major types of bronchopulmonary receptors, namely slowly- experiments to test whether the few published tools used to mod- adapting (SARs) and rapidly-adapting stretch receptors (RARs) and ulate RAR or SAR function are operative in lambs.
C-fiber endings (CFEs). The complex effects of lung inflation on these receptors have been summarized as follows Slowly-adapting receptors are stimulated 2. Materials and methods
by moderate lung inflation and are involved in the inspiratory switch-off during normal breathing. RAR stimulation is usually sec- ondary to rapid, large lung inflations, but can be seen even during Nine male lambs aged 4–6 days and weighing 4.6 ± 0.8 kg were involved in the study. All lambs were housed in a Plexiglas chamber, where they were able to move freely and bottle-feed ad libidum on ∗ Corresponding author. Tel.: +1 819 346 1110x14851; fax: +1 819 564 5215.
reconstituted ewe milk. The study was approved by the Ethics Com- E-mail address: (J.-P. Praud).
mittee for Animal Care and Experimentation of the Université de 1569-9048/ 2014 Published by Elsevier B.V.
N. Samson et al. / Respiratory Physiology & Neurobiology 202 (2014) 32–34 Sherbrooke (protocol # 037-10), in accordance with the Canadian Council on Animal Care guidelines.
Cardiorespiratory responses following capsaicin IV injection before (intact C-fibers; 10 ␮g/kg) and after C-fiber blockade (50 ␮g/kg).
C-fiber blockade 2.2. Surgical instrumentation and study design Apnea duration (s) Bradycardia duration (s) Chronic instrumentation was performed under general anes- Tachypnea, no of respiratory cycles/min thesia as previously detailed (in order to measure Results are expressed as mean ± SD.
states of alertness, electrical activity of the thyroarytenoid muscle (EaTA, a glottal constrictor), tracheal PetCO 3.2. Inspiratory laryngeal narrowing during nPSV 2, arterial blood gases and respiratory movements (inductance plethysmography). Two days later, in order to fulfill our first study aim, two polysomno- Eight of nine lambs with intact CFEs presented with inspiratory graphic recordings during nPSV 15/4 cmH EaTA during nPSV 15/4 cmH in quiet sleep. As illustrated in 2O (Servo-i ventilator; inspiratory pressurization time = 0.12 s) were performed on two CFE blockade did not prevent the occurrence of inspiratory EaTA consecutive mornings, before (intact CFEs) and after CFE blockade, (74 ± 41% vs. 64 ± 35% of respiratory cycles, p = 0.5). No differences in non-sedated lambs. Neonatal injection of high doses of capsaicin were noted for PaCO2 and PaO2 (respectively p = 0.4 and p = 0.6) is well known to induce both a selective degeneration and func- between before and after CFE blockade.
tional ablation of CFEs (which we previously confirmed in newborn lambs Accordingly, CFEs 3.3. Attempts at selectively blocking RARs were blocked on the first recording afternoon by a subcutaneous injection of 25 mg/kg of capsaicin (diluted in 10% Tween 80, 10% Intravenous infusion of dopamine in two blocked-CFE lambs ethanol and 80% physiological saline) under a 30-min general anes- did not alter the cardiorespiratory responses to RAR stimulation, thesia. The integrity of bronchopulmonary CFEs was assessed by while the highest doses induced arterial hypertension. Similarly, inducing pulmonary chemoreflexes by intravenous (IV) injections inhaled furosemide did not alter the responses to RAR stimulation.
of 5 and 10 ␮g/kg capsaicin under intact CFE conditions, while effec- As expected, no alteration of the Hering–Breuer inspiratory reflex tive CFE blockade was verified by IV injection of 50 ␮g/kg capsaicin was observed with either dopamine or furosemide.
Following completion of the above experiments, selective blockade of RAR function was attempted in the last four non- sedated lambs. Increasing doses of dopamine (n = 2, IV infusion The present study shows that the active inspiratory laryngeal from 50 up to 200 ␮g/kg/min, after premedication with IV phen- narrowing observed during nasal pressure support ventilation in tolamine + propanolol to prevent severe arterial hypertension) lambs does not originate from the stimulation of bronchopul- or inhaled furosemide (n = 2, dose monary C-fiber endings.
from 60 to 100 mg) (were administered. RAR function was assessed via analysis of cardiorespiratory responses 4.1. Inspiratory laryngeal narrowing during nPSV (number of coughs, apnea and bradycardia duration) to an intra- tracheal injection of 0.5 mL distilled H2O. Finally, assessment of Over the past decade, we have shown in several studies that an the Hering–Breuer inspiratory reflex (delayed onset of inspiration active inspiratory narrowing develops against ventilator insuffla- after nasal mask occlusion at end-inspiration) was also performed tions during nPSV (15/4 cmH in at least two thirds of full-term to confirm the absence of altered SAR function.
lambs in quiet sleep and quiet wakefulness These results are in keeping with a recent review suggesting that this active inspiratory laryngeal narrowing 2.3. Data and statistical analyses can be responsible for significant patient-ventilator asynchrony, patient discomfort and non-invasive ventilation failure. As a result, The number of respiratory cycles with inspiratory EaTA further study of the mechanisms of this larynx-ventilator asyn- during a period of 60 s of quiet sleep was determined dur- chrony has been advocated ing nPSV 15/4 cmH2O. The cardiorespiratory responses of the We previously documented that active inspiratory laryngeal pulmonary chemoreflex, classically characterized by central narrowing during nPSV originates from bronchopulmonary recep- apnea/bradycardia followed by tachypnea, were also analyzed.
tors (The short burst of EaTA, disappearing well The percentage of inspiratory EaTA as well as the cardiore- before the end of the inspiratory pressure plateau in nPSV (see Fig.
spiratory responses following an IV injection of capsaicin were 3 in does not suggest the involve- compared before and after CFE blockade using the Wilcoxon ment of SAR. While both RARs and CFEs are also stimulated by signed-rank test. Differences were considered significant if p < 0.05.
lung distension (our previous Data are expressed as mean ± SD.
observation that stimulation of pulmonary CFEs in lambs triggers post-inspiratory EaTA together with the avail- ability of our robust lamb model with blocked CFEs, prompted us 3. Results
to assess the potential involvement of CFEs in inspiratory laryngeal narrowing during nPSV. The present demonstration that CEFs are 3.1. Effectiveness of C-fiber blockade not involved leads us now to suggest that this inspiratory laryngeal narrowing most likely originates from RAR stimulation.
In lambs with intact CFEs, 10 ␮g/kg capsaicin IV consistently induced pulmonary chemoreflexes with apnea + bradycardia last- 4.2. Attempts at selectively blocking RARs ing up to 11 s and preceding tachypnea (218 ± 53 respiratory cycles/min). This biphasic cardiorespiratory response was abol- A systematic review of the literature revealed that IV dopamine ished in all lambs after CFE blockade, even following 50 ␮g/kg (and inhaled furosemide selectively block RARs, respectively in anesthetized adult

N. Samson et al. / Respiratory Physiology & Neurobiology 202 (2014) 32–34 Fig. 1. (A) Glottal constrictor activity (EaTA) during nasal support ventilation (nPSV) 15/4 cmH2O before (intact C-fibers; left panel) and after C-fiber blockade (right panel).
Abbreviations from top to bottom: EaTA, electrical activity of the thyroarytenoid muscle; EaTA, moving time averaged EaTA; Pmask, mask pressure; Ptrach, tracheal pressure; Vlung, lung volume variations, given by the sum signal of the respiratory inductance plethysmography (inspiration upwards); i: inspiration; e: expiration. (B) Percentage of respiratory cycles with inspiratory EaTA (% Inspir EaTA) before and after C-fiber blockade. Results reveal that blockade of bronchopulmonary C-fibers does not prevent inspiratory EaTA during nPSV 15/4 cmH2O.
dogs and rats. Unfortunately, we were unable to reproduce these of the Canada Research Chair in Neonatal Respiratory Physiology results in lambs; such discrepancies may be related to differences and a member of the Centre de recherche du Centre hospitalier uni- in species, maturation and/or the use of anesthetics, all of which versitaire de Sherbrooke.
have previously been shown to affect bronchopulmonary receptors A more comprehensive assessment of the three major types of bronchopulmonary receptors should include experimental modu- Coleridge, J.C.G., Coleridge, H.M., 1984. lation of SAR function. To our knowledge, the only report of SAR blockade in the literature involved the use of SO 2 inhalation. How- Coleridge, H.M., Coleridge, J.C.G., 2011. ever, while the latter was successful in adult rabbits anesthetized with urethane, it was unsuccessful in newborn rabbits, in adult dogs and cats as well as in adult rabbits when using a different anesthetic Diaz, V., Dorion, D., Renolleau, S., Létourneau, P., Kianicka, I., Praud, J.P., 1999. agent Given these results and the current ban on urethane use due to its toxicity, no attempt was made to block SARs in lambs.
Jackson, D.M., Simpson, W.T., 2000. Jancso, G., Kiraly, E., Jancso-Gabor, A., 1977. Moreau-Bussière, F., Samson, N., St-Hilaire, M., Reix, P., Lafond, J.R., Nsegbe, E., Praud, The present results showing that active inspiratory laryngeal narrowing during nasal pressure support ventilation does not orig- inate from bronchopulmonary C-fiber endings suggest the likely Mortola, J.P., Fisher, J.T., Sant'Ambrogio, G., 1984. involvement of bronchopulmonary rapidly adapting receptors.
However, in the absence of available tools enabling the selective Oppersma, E., Doorduin, J., van der Heijden, E.H., van der Hoeven, J.G., Heunks, blockade of these receptors in lambs, such involvement remains to be demonstrated.
Roy, B., Samson, N., Moreau-Bussière, F., Ouimet, A., Dorion, D., Mayer, S., Praud, Sudo, T., Hayashi, F., Nishino, T., 2000. This study was supported by the Canadian Institutes of Health Research (Grant no. IRSC RS-286032). Jean-Paul Praud is the holder

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