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Laryngeal chemoreflexes induced by acid, water, and saline in nonsedated newborn lambs during quiet sleep

Neonatal Respiratory Research Unit, Departments of Pediatrics and Physiology, University of Sherbrooke, Quebec, Canada

Submitted 2 December 2004 ; accepted in final form 14 February 2005

	ABSTRACT

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Laryngeal chemoreflexes (LCR) are triggered by the contact of assorted liquids with the laryngeal mucosa. In the neonatal period, the immature LCR consist primarily of apnea and bradycardia, which at times can be life threatening. The aim of this study was to assess LCR induction in nonsedated, newborn full-term lambs by several acid solutions, compared with distilled water and saline. Twelve lambs were instrumented for recording of glottal adductor and diaphragm EMG, EEG, eye movements, heart rate, systemic arterial pressure, and respiratory movements. LCR were induced during quiet sleep by the injection (0.5 ml) of saline, distilled water or two acid solutions (HCl and citric acid, pH 2, diluted in either water or saline). A chronic supraglottal catheter was used to inject the solutions in a random order. Distilled water and acid solutions did not induce any significant decrease in heart rate or respiratory rate. However, significant lower airway protective responses (swallowing, cough, and arousal) were observed after distilled water and especially acid solution administration. In conclusion, LCR in full-term lambs, particularly with acid solutions, are merely characterized by lower airway protective responses resembling mature LCR reported in adult mammals.

apnea; bradycardia; apparent life-threatening event

	MATERIALS AND METHODS

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Animals.   Experiments were performed in 12 lambs aged 2–3 days and weighing 4.6 kg (SD 0.9) at time of surgery. All lambs were born at term and housed with their mothers in our animal quarters. The protocol of the study was approved by our institutional Ethics Committee for Animal Care and Experimentation.

Instrumentation of the lambs.   Surgery was performed 2 days before experimentation under general anesthesia (2% isoflurane, 30% N₂O, and 68% O₂). Atropine sulfate (0.1 mg/kg), ketamine (10 mg/kg), and ketoprofen (3 mg/kg) were injected intramuscularly before anesthesia. Antibiotics (0.05 ml/kg benzylpenicillin and 5 mg/kg gentamicin) were also injected intramuscularly before anesthesia and each day throughout the study. One lamb received one intramuscular injection of dexamethasone (0.5 mg/kg) 1 day after surgery to decrease laryngeal inflammation manifested by weak bleating. Bipolar enameled chrome wire electrodes were inserted into the thyroarytenoid (TA, a glottal adductor) and diaphragm muscles for recording of electrical activity (EMG) (14), together with custom-designed electrodes for EEG (EEG) recordings (30). A cup electrode was also inserted under the scalp as a ground. Leads from each electrode were subcutaneously tunneled to exit on the back of the lambs. Correct positioning of electrodes in laryngeal and diaphragmatic muscles was always verified at autopsy. In addition, a supraglottal catheter was inserted to allow injection of liquids onto the larynx. The catheter was adapted from an infusion catheter and placed by using a modified Seldinger technique with a metal guide wire inserted transcutaneously through the base of the epiglottis, as described previously (6). The tip of the catheter was positioned 5–7.5 mm above the anterior part of the glottis, whereas the external part of the catheter protruded 15–20 mm at the level of the anterosuperior aspect of the thyroid cartilage. The catheter was held in place by two rings, including one internal ring made of thick, rapid-drying adhesive glue, and an external ring made from the rubber end of a 3-ml syringe. Proper catheter positioning above the glottis was monitored throughout the insertion procedure by direct laryngoscopy and was systematically confirmed during autopsy. Finally, an arterial catheter was inserted into the brachial artery for recording systemic arterial pressure. All lambs were returned to their mother after arousal from anesthesia.

Additional instrumentation was performed immediately before initiation of the experiments, all of which were performed in nonsedated lambs. Nasal airflow was recorded by use of a thermocouple wire (iron/constantan, type J; Omega Engineering, Stamford, CT) glued to the side of one nostril. Two platinum needle electrodes (E2-12, Grass Instrument, Quincy, MA) were respectively placed subcutaneously into the outer upper region and the inner lower region of the right eye socket for electrooculogram (EOG) recording. Three platinum needle electrodes (two on the proximal forelegs and one on the proximal left hind leg) were inserted subcutaneously for recording ECG. Thoracic and abdominal bands were placed for recording respiratory inductance plethysmography (Respitrace, NIMS, Miami Beach, FL). Finally, an oximeter probe (8000R reflectance sensor, Nonin Medical, Plymouth, MN) was attached at the base of the tail for continuous monitoring of pulse oximetry.

Recording equipment.   Leads from the EMG, EOG, and EEG electrodes and the nasal thermocouple were connected to a transmitter attached to the lamb's back just before the experiment. Raw EMG, EOG, and EEG signals and nasal flow were transmitted by radiotelemetry by using custom-designed equipment (16). Raw EMG signals were moving time averaged (100 ms) via the acquisition software (Acknowledge Version 3.2, Biopac System, Santa Barbara, CA). Systemic arterial pressure was obtained from the brachial catheter using a pressure transducer (Trantec model 60-800, American Edwards Laboratories, Santa Anna, CA) and pressure monitor (model 78342A Hewlett-Packard, Waltham, MA). Lead II ECG was also obtained using this monitor. Thoracic and abdominal volume variations were qualitatively assessed by using respiratory inductance plethysmography. Oxygenation was continuously monitored via our custom-designed pulse oximeter built from a Nonin OEM with transmission by radiotelemetry (28). All parameters were continuously recorded by an Apple Macintosh microcomputer and the Acknowledge software. Collected data were stored on compact disk for further analysis.

Design of the study.   The study was designed to allow for simultaneous recording of TA and diaphragmatic EMG, ECG, EEG, EOG, nasal flow, sum of thoracic and abdominal movements, and arterial pressure. Lambs were left with their mothers and fed ad libitum until preparation for the experiment. Lambs were comfortably positioned in a sling with loose restraints (Fig. 1). Ambient temperature was kept at 22°C and humidity at 70% throughout the experimental days. Experiments were performed in nonsedated lambs over 2 consecutive days (i.e., postnatal age 4 and 5 days or 5 and 6 days). For the first eight lambs, each experimental day consisted of a random sequence of eight laryngeal stimulations with four different solutions, totaling four injections of each solution at the end of the 2 experimental days. Stimulations were performed only during quiet sleep by injecting either hydrochloric acid (HCl) diluted in distilled water (pH = 2), citric acid diluted in distilled water (pH = 2), distilled water, or saline (0.9% NaCl, pH 5.5, used as control) through the supraglottal catheter (Table 1) In addition, two other solutions were also injected in the last four lambs [HCl diluted in saline (pH = 2), and citric acid diluted in saline (pH = 2)], totaling 12 injections per day of experimentation. Before injections, all solutions were warmed and maintained at the lamb's body temperature by use of a heating bath. To inject a volume of 0.5 ml onto the larynx, the actual volume of the solutions injected through the supraglottal catheter was 0.9 ml (dead space of the catheter = 0.4 ml). In addition, the catheter was systematically flushed with 1 ml of saline between injections. Each animal was given at least 10 min of recovery time between two injections. Events such as agitation, cough, and overt arousal or full awakening were noted by an observer throughout the recording sessions. Finally, 0.5 ml of methylene blue was injected through the supraglottal catheter after completion of the experiments, to verify that the instillations were limited to the supraglottal area (no staining beneath the glottis).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Schematic representation of the experimental design. Ta, raw electrical activity of the thyroarytenoid muscle; Di, raw electrical activity of the diaphragm.

Statistical analysis.   Measurements were first averaged in each lamb (mean of 4 injections for each stimulus) and then averaged for the 12 lambs as a whole. Values were then expressed as means and SD. For all parameters, except for % LCR with apnea(s), cough, arousal, and awakening, differences in responses between the various laryngeal stimuli were assessed by one-factor ANOVA for repeated measures, completed by Fisher's paired least significant difference test, when indicated. For % LCR with apnea(s), cough, arousal, and awakening, statistical analyses were performed using the SAS software package; effects of age and solution were tested by means of generalized estimating equation models, i.e., generalized models with repeated measures (GENMOD procedure of SAS). The working correlation structure chosen was the exchangeable type. With the response variable being a proportion, generalized linear model consisted of a logistic regression with a logit link function. For all parameters, a P < 0.05 was considered as statistically significant.

	RESULTS

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General results.   A total of 203 laryngeal stimulations (46 saline, 45 distilled water, 48 HCl in water, 39 citric acid in water, 12 HCl in saline, and 13 citric acid in saline) were performed in the 12 lambs during quiet sleep. Twenty-five stimulations (6 saline, 4 distilled water, 8 HCl in water, 5 citric acid in water, 1 HCl in saline, and 1 citric acid in saline) could not be completely analyzed, because of either important agitation or coughing movements or loss of signal. Results are reported in Table 2. All solutions, including saline, elicited a consistent sequence of events occurring within 10 s of laryngeal stimulation. Regardless of stimulus, arousal (when present) occurred immediately after liquid instillation, and swallowing activity (when present) began in the first 2 s after liquid instillation. Thereafter, a decrease in RR and an increase in MAP were consistently observed, followed by a decrease in HR. Hence, occurrence time of HR_min was significantly delayed, compared with those of RR_min and MAP_max (P = 0.1, RR_min vs. MAP_max; P < 0.0001, RR_min vs. HR_min; P < 0.0001, MAP_max, vs. HR_min). There were no differences in results observed among days 4, 5, and 6 of age.

View larger version (35K): [in this window] [in a new window]   Fig. 2. Laryngeal chemoreflexes in response to instillation of 0.5 ml saline onto the laryngeal mucosa in a nonsedated newborn lamb during quiet sleep. Nasal flow, nasal airflow; Lung volume, sum signal of the respiratory inductance plethysmograph, allowing qualitative measurement of respiration (inspiration upward); AP, systemic arterial pressure; ECG, electrocardiogram; EEG, electroencephalogram; EOG, electrooculogram.

View larger version (36K): [in this window] [in a new window]   Fig. 3. Laryngeal chemoreflexes in response to instillation of 0.5 ml of citric acid diluted in water onto the laryngeal mucosa during quiet sleep (same lamb as in Fig. 2). Apart from the initial EMG activity observed just after instillation of acid, each burst of Ta muscle EMG represents a swallow. See Fig. 1 for abbreviations.

Acids diluted in saline.   Results in the four lambs in which HCl and citric acid diluted in both distilled water and saline were tested are reported in Table 3. Overall, identical cardiorespiratory responses were induced by HCl and citric acid, whether they were diluted in water or saline. Apneas, as assessed by the percentage of stimulations with apneas and total apnea duration, were identical irrespective of whether acids were diluted in water or saline. LCR respiratory duration, however, was greater in HCl in water than in saline (HCl diluted in water, P = 0.007). Although swallowing activity and total TA EMG were identical regardless of dilution in water or saline, total TA EMG duration was lower after HCl than citric acid. Cough bursts were mostly observed after both citric acid solutions, and to a lesser degree after distilled water and HCl diluted in water; cough was absent after HCl diluted in saline. Total LCR duration after citric acid diluted in saline was greater than after HCl diluted in water (P = 0.02) or saline (P = 0.02). Finally, arousal from quiet sleep was observed in more than 80% of cases after acid injection, whether diluted in water or saline. However, full awakening appeared less frequent with HCl diluted in saline than with the other acid solutions.

	DISCUSSION

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The present study brings unique perspectives on LCR induced in newborn lambs in highly standardized conditions. Overall, our findings reveal that in nonsedated, full-term lambs during quiet sleep, cardiorespiratory components of the LCR were mild and similar after instillation of both distilled water and acid solutions. However, acid solutions elicited lower airway protective reflexes of greater amplitude than distilled water, including swallowing, cough, and arousal, suggesting that acid solutions (especially citric acid) are more potent stimuli than distilled water.

Uniqueness of our study in lambs.   Review of the literature has yielded an estimated 50 studies assessing LCR in newborn mammals, including human infants. From these studies, we were able to find only 11 studies performed in the absence of anesthesia and sedation, either in lambs or piglets (8, 9, 18, 19, 20, 22, 33) or in human infants (3, 23, 25, 26). However, two of these studies did not take into account state of alertness (3, 9), although two others injected liquids through a tracheostomy toward the subglottal region (8, 18), hence putting in question the specificity of the receptors (supraglottal, subglottal, and/or tracheobronchial?) responsible for the reported LCR. In addition, despite the clinical relevance of acid solutions at this age because of the possibility of acid gastroesophageal reflux, only two of the above reports actually compared acid solutions with saline and/or water (20, 22), whereas the others used only saline and/or water injections. Hence, to our knowledge, only one previous study performed in piglets (22) is comparable to our present study in lambs with regard to the absence of sedation, the recording of the states of alertness, and comparison of an acid solution to both saline and water (22). However, further consideration of the latter study shows that our study design allows the most complete study to date of LCR in nonsedated newborn mammals, because of the assessment of four acid solutions (2 acids, 2 solvents) vs. both saline and water, the control of the exact site of injection, and the exhaustive analysis of the responses.

LCR induced by distilled water.   Since the first observation by Johnson et al. (10) in anesthetized lambs, numerous studies have shown that the cardiorespiratory responses to application of water on the laryngeal mucosa are especially pronounced in newborn mammals (32, 34). In contrast to water, saline was repeatedly shown to elicit very mild or no responses. Results of the present study confirm that saline induces virtually no cardiorespiratory responses. Moreover, present findings also show that saline induces virtually no swallowing, TA EMG activity, cough, or arousal. Conversely, our results confirm that distilled water induces significantly more pronounced cardiorespiratory responses than saline, including a decrease in RR (occasionally up to short apnea), a decrease in HR, and an increase in MAP. In addition, TA EMG activity after water was significantly greater than after saline injection. However, the cardiorespiratory responses recorded with water were less pronounced than that traditionally reported in the literature. For example, distilled water was reported to induce prolonged apnea followed by gasping and sometimes death in anesthetized piglets (4, 15). With regard to cardiovascular responses, water was reported to induce a 44% decrease in HR and a 31% increase in MAP in nonsedated, awake lambs (8), which represent alterations well above those observed in the present study. Discrepancies between these previous results and ours with respect to cardiorespiratory responses are most likely related to the use of anesthesia and/or the greater volume of water injected (15 ml vs. 0.5 ml) and/or the site of injection (subglottal vs. supraglottal) in previous studies. Accordingly, results in nonsedated piglets using a volume of water closer to that used herein yielded similarly mild cardiorespiratory responses (22). Finally, present results showing that swallowing and arousal were more often observed after water than saline are in agreement with previous studies (3, 22).

LCR induced by acid solutions.   Overall, aside from more frequently observed short apneas after distilled water than after acid solution, the cardiorespiratory responses elicited by distilled water and HCl were identical, which is in agreement with results in piglets (22). On the other hand, citric acid induced a significantly greater decrease in HR than either distilled water or HCl. The reason for this difference is currently unknown. Conversely, protective lower airway mechanisms were more apparent after injection of acid solutions than distilled water. Indeed, arousal and full awakening, cough, and total LCR duration were significantly more pronounced with acid solutions than with distilled water or saline. Although we have verified that the solutions did not reach the subglottal area (systematic injection of methylene blue after completion of the experiments), it is still possible that some aerosolized or vaporized acid solutions penetrated the lower airways and triggered reflexes such as cough (5). Conversely to our present results, swallowing activity was reported to be more prominent with water than HCl (pH 2) in piglets during natural sleep (22). However, our results are in agreement with a previous study in adult rats, showing that swallowing is more marked after pharyngeal infusion of citric acid than distilled water (12). This latter observation was interpreted as being related to the sour taste of citric acid, an assertion that this study does not allow to elaborate.

Although the study of solutions composed of acids diluted in water may represent the maximal stimulus for LCR (stimulation by both water and acid), a comparison of the responses elicited by acids diluted in saline allows to better explore the LCR triggered by acid stimulus alone. Analysis of the results suggests that both saline and water solutions invariably trigger identical LCR. On the other hand, for unknown reasons, LCR elicited by citric acid solutions appear to be more pronounced than LCR elicited by HCl.

Differences between responses to distilled water and acid solutions are probably primarily related to stimulation of different laryngeal receptors. Boggs and Bartlett (2) initially demonstrated that cardiorespiratory responses induced by contact of distilled water with the laryngeal mucosa are related to low chloride concentrations. Since then, two types of water receptors have been described in the laryngeal mucosa, including a short-latency receptor, which responds to low chloride concentrations (rapidly adapting receptor), and a long-latency receptor, which responds to hypoosmolality (1). Conversely, protons have been shown to stimulate different receptors, namely the acid sensing ion channels and the vanilloid receptor, which are present on both C and A-fibers (11, 17, 27,). As for the larynx, C-fiber endings have been shown to be sensitive to citric acid in adult guinea pigs (5) but insensitive to water in adult dogs (21) and guinea pigs (5). Our previous results in lambs suggest that laryngeal C fibers are already functional in the neonatal period and are insensitive to water (31).

In conclusion, full-term lambs appear to have mature LCR, characterized by lower airway protective mechanisms and absence of clinically significant apnea-bradycardia. Reasons for the apparent discrepancy with most previous studies in newborn mammals are predominantly related to experimental conditions. Our observations of very mild cardiorespiratory responses in full-term lambs but of clinically significant apnea-bradycardia after acid solutions in preterm lambs (preliminary observations) are in agreement with clinical observations in full-term and preterm human infants. Further studies will be needed, however, to further delineate clinically relevant conditions known to exacerbate LCR, as well as to study the neuronal mechanisms responsible for LCR triggered by acid solutions, equally for its clinical relevance.

	GRANTS

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The experiments were supported by Canadian Institute of Health Research Operating Grant MT 15558 and the Quebec Foundation for Research into Children's Diseases. M. St-Hilaire is an MSc scholar from the Respiratory Research Network, Fonds de la Recherche en Santé du Québec. J.-P. Praud is a national scholar of the Fonds de la Recherche en Santé du Québec.

	ACKNOWLEDGMENTS

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The authors gratefully acknowledge the expert technical assistance of Christophe Grenier and Jean-Philippe Gagné and the assistance of Marie-Pierre Garant for statistical analyses.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J.-P. Praud, Depts. of Pediatrics and Physiology, University of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4 (E-mail: Jean-paul.praud{at}usherbrooke.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

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This Article Abstract Full Text (PDF) Free All Versions of this Article: 98/6/2197    most recent 01346.2004v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by St-Hilaire, M. Articles by Praud, J.-P. Search for Related Content PubMed PubMed Citation Articles by St-Hilaire, M. Articles by Praud, J.-P.