Laryngeal Chemoreflex Research Articles

Improved recovery from laryngeal-stimulation-induced apnea by alpha-adrenergic blockade in adult rabbits.

The apnea triggered by laryngeal stimulation (LS) is associated with a redistribution of blood flow towards the heart and the brain that depends upon peripheral vasoconstriction. The circulatory component of the response to LS has been shown to be reduced following injection of large dose of beta-adrenergic agonist that more intriguingly blunted the ventilatory response as well. To test whether the reduction of LS-induced apnea could be related to the decreased magnitude of the peripheral vasoconstruction, the effects of the alpha-adrenergic antagonist urapidil on the ventilatory and blood pressure responses to LS were studied in 6 adult rabbits. alpha-Adrenergic blockade reduced both the rise in blood pressure and the magnitude of hypopnea induced by LS. These results suggest that the circulatory component of the laryngeal chemoreflex, i.e. the peripheral vasoconstruction, contributes to the magnitude of the ventilatory depression.

The effect of antitastamines on the laryngeal chemoreflex

The laryngeal chemoreflex (LCR) consists of apnea, laryngospasm, and cardiovascular changes in neonates after laryngeal irritation and has been implicated in sudden infant death syndrome and apnea of infancy. Antihistamines attenuate a similar vagally mediated pulmonary chemoreflex. The intravenous antihistamine effect on the LCR was studied in neonatal piglets. Laryngeal muscle activity, respiration, blood pressure, and pulse were measured during water stimulation of the LCR. After baseline LCR recordings, intravenous diphenhydramine (2.5 mg/kg) or cimetidine (20 mg/kg) was bolused (control group received saline). LCR measurements were repeated over 7 hours. Diphenhydramine significantly shorted apneas (P < .05) 3 to 7 hours after drug bolus, which is believed to be secondary to central atropinic effects. Cimetidine demonstrated no attenuation of the LCR.

Beta-endorphin may be a mediator of apnea induced by the laryngeal chemoreflex in piglets.

To determine whether beta-endorphin is involved in the laryngeal chemoreflex, we initially injected 0.01-1 mg of beta-endorphin into the cisterna magna (i.c.m.) and registered the respiratory and cardiovascular patterns in 5-10-d-old piglets. From 0.1 to 1 mg of beta-endorphin i.c.m. induced a decrease in the minute volume, heart rate, and blood pressure within 15 min. Within the next 30 min respiratory pauses accompanied by blood pressure increases and reductions in heart rate developed, similar to the respiratory and cardiovascular pattern of the induced laryngeal chemoreflex. Based on these initial data, we decided to induce a laryngeal chemoreflex in piglets pretreated with 0.1 mg of beta-endorphin i.c.m (n = 6), 0.2 mg of beta-endorphin i.c.m. (n = 6), 0.1 mg of beta-endorphin i.c.m. and 100 micrograms/kg naloxone i.v. (n = 6), 100 micrograms/kg naloxone i.v. (n = 6), or water i.c.m. (n = 6). Because elevated levels of hypoxanthine in the vitreous humor may indicate hypoxia before death, we therefore measured the postmortem hypoxanthine levels in the vitreous humor. The laryngeal chemoreflex-induced apnea was shortened in the piglet group pretreated with water i.c.m and naloxone i.v. (p < 0.01) and in the piglet group pretreated with 0.1 mg of beta-endorphin i.c.m and naloxone i.v. (p < 0.05), but not significantly prolonged in the piglet groups pretreated with 0.1 or 0.2 mg of beta-endorphin i.c.m. when compared with the piglets pretreated with water i.c.m.(ABSTRACT TRUNCATED AT 250 WORDS)

20: The Effect of Medical Treatment of Gastroesophageal Reflux on the Severity of Obstructive Sleep Apnea

Objective: To determine the extent to which gastroesophageal reflux (GER)—initiated laryngeal chemoreflexes contribute to obstructive sleep apnea (OSA). Methods: This study is a prospective clinical trial of an antireflux treatment protocol as a means of reducing the severity of OSA. The study population consists of male patients, ages 20 to 64 years, who have not received prior treatment for OSA or GER. Patients undergo ambulatory pH probe monitoring and overnight polysomnography. Patients with evidence of both GER and OSA are treated for 30 days with omeprazole, 20 mg by mouth twice daily, as well as a standard antireflux regimen. After this treatment, patients undergo repeat polysomnography to document changes in apnea index (AI), hypopnea index (HI), respiratory disturbance index (RDI), and minimum oxyhemoglobin saturation. Results and Conclusions: Changes in AI, HI, RDI, and minimum oxyhemoglobin saturation will be presented and discussed, as will the use of antireflux medications as a modality for the treatment of OSA.

221 NALOXONE INHIBITS THE DURATION OF THE LARYNGEAL CHEMOREFLEX (LCR) ACTIVATED APNEA IN PIGLETS

Beta-endorphin may induce respiratory depression and bradycardia. Infants with apnea and increased level of beta-endorphin immuno-reactivty in CSF have been succesfully treated with naloxone. Therefore, LCR apnea was activated in five groups of 5-10 days old piglets: 1) untreated n=6 (CONTR), 2) 0.1mg beta-endorphin in cist.erna maqna (L.c.m.) n = 6, (END) 3) 0.2mg beta-endorphin i.c.m n=6 (END X 2), k) 100 mikrogr/kg naloxone n=6 (NAL), 5) 0.1mg beta-endorphin i.c.m. and naloxone nr6 (END NAL). Respiration, heart rate, 6 and blood pressure were monitored. We found that 0.1-0.2mg beta-endorphin induced apneas nnd bradycardia and hypertension. Furthermore, naloxone shortened the induced LCR.Conclusion: Naloxone inhibils laryngeal chemoreflex induced apnea.

Influence of hypoxia on ventilatory responses to intralaryngeal CO 2 in cats

In decerebrate, vagotomized cats, induction of CO 2 into the isolated laryngeal airway while systemic P CO2 is held constant evokes dose-related reflex changes in ventilatory activity. Because systemic hypoxia is known to exaggerate ventilatory responses to other types of laryngeal chemo- stimulation in neonates, we have compared the responses of phrenic and hypoglossal nerve activities to ventilation of the larynx with 10% CO 2 during systemic hyperoxia (Fi o 2 = 1.00) to those during hypoxia (Fi o 2 = 0.12). Compared with hyperoxic baseline condition, hypoxia stimulated phrenic activity but attenuated the reduction in phrenic activity evoked by intralaryngeal CO 2. Hypoglossal activity was increased by intralaryngeal CO 2 and this response appeared to be reduced by hypoxia, but neither of these findings was statistically significant. The response of phrenic activity to intralaryngeal CO 2 during systemic hypercapnia was similar to that during hypoxia. The increase of phrenic activity in response to hypoxia was prevented by carotid body resection. Similarly, the hypoxic attenuation of the phrenic response to intralaryngeal CO 2 appeared to be absent after carotid body resection, although this finding was not established statistically. These results differ from previous reports of exaggerated laryngeal chemoreflex responses during hypoxia. The difference may reflect differences in the receptors and synaptic mechanisms of the reflexes, the severity and time course of hypoxia or the presence or depth of general anesthesia or sleep.

Fine structure of taste buds located on the lamb epiglottis

Taste buds located on the aryepiglottal folds and laryngeal surface of the epiglottis are the principal receptors responsible for the initiation of the laryngeal chemoreflex. In contrast to the wealth of information available concerning the ultrastructure of oral taste buds, little comparable data exists for taste buds located at the entrance to the larynx. Therefore, the present study was designed to investigate the fine structure of taste buds located on the lamb epiglottis. Stained thick and semi-serial thin sections from taste buds located on the lamb epiglottis were examined with light and electron microscopy. Based on morphological criteria, three types of cells could be identified in the taste bud: Type I, Type II, and basal cells. Both Type I and Type II cells extended into the apical taste pore, but there were differences between these two cell types with regard to nuclear profiles, electron density, and the relative density of ribosomes, apical mitochondria, and rough and smooth endoplasmic reticulum. Basal cells did not extend a process into the taste pore. Nerve processes were observed throughout the taste bud. Synapses were observed between both Type I and Type II cells and nerve fibers. These synapses exhibited membrane thickenings and accumulations of clear and dense-cored vesicles of varying proportions in the taste cell cytoplasm adjacent to membrane specializations. The taste buds located on the lamb epiglottis share several structural similarities to taste buds located in the oral cavity and other regions of the pharynx and larynx of many mammalian species. The presence of synapses on both Type I and Type II cells of the lamb epiglottal taste bud suggests that both cell types are involved in laryngeal chemoreception.

Reflex laryngospasm induced by stimulation of distal esophageal afferents

Distal esophageal sensory nerves were stimulated in 17 anesthetized dogs divided into three age groups to determine the laryngeal, cardiovascular, and respiratory effects. Group I puppies were 5 to 6 weeks of age, group II puppies were 8 to 19 weeks of age, and group III animals were adult dogs. Marked laryngeal adductor activity and laryngospasm were observed in group II puppies, while no or minimal laryngeal adduction was seen in younger puppies and adult dogs. Mean arterial pressure and heart rate increased significantly in groups II and III (P < .005) but remained unchanged in group I animals (P > .4). This response is distinctly different from the laryngeal chemoreflex because central apnea, hypotension, and bradycardia were absent. The afferent limb of the response is mediated by the vagus nerve as bilateral transthoracic truncal vagotomy eliminated the reflex. The laryngeal response observed following stimulation of distal esophageal afferent fibers may be important in the mechanism of apparent life-threatening events (ALTEs) and the sudden infant death syndrome (SIDS) associated with gastroesophageal reflux disease.

Prolonged hypoxemia enhances and acute hypoxemia attenuates laryngeal reflex apnea in young lambs.

To determine the influence of an altered carotid body function on the laryngeal chemoreflex (LCR) response, reflex apnea was induced by laryngeal water stimulation during normoxia or acute hypoxia in unanesthetized awake lambs in which the ventilatory response to acute hypoxia was attenuated by prolonged postnatal hypoxemia. Prolonged hypoxemia (H) was induced in seven lambs for 12 d after birth through exposure to 0.10 fraction of inspired oxygen. Five control lambs were kept in 0.21 fraction of inspired oxygen. Studies were performed repeatedly during the first 7 wk after birth. The ventilatory response to LCR stimulation, expressed as a percent decrease in minute ventilation, was tested in 0.21, 0.14, and 0.10 fraction of inspired oxygen. H after birth resulted in a markedly increased inhibition of ventilation in response to LCR stimulation and postponed the age-related decrease in LCR response. A potential failure to recover from apnea occurred only in the H lambs, and in these lambs there was a significantly greater requirement for mechanical ventilation after LCR stimulation. Acute hypoxemia preceding LCR stimulation significantly attenuated the ventilatory response in both control and H lambs, with a stronger effect in the H lambs. There was no difference between the two groups in heart rate response to LCR stimulation. Acute hypoxemia significantly augmented reflex bradycardia in the H lambs. These results show that there is a relationship between H immediately after birth--which is known to delay resetting of carotid chemoreceptors--and augmented ventilatory inhibition in response to LCR stimulation. They do not confirm the theory that acute hypoxia reinforces reflex apnea.

Cholinergic agents in the laryngeal chemoreflex model of sudden infant death syndrome.

The laryngeal chemoreflex results in apnea, laryngospasm, and cardiovascular changes that can be fatal when a liquid stimulus is placed on the laryngeal mucosa of infant mammals. This study of 35 piglets assessed the effects of the cholinergic agents atropine and edrophonium on this laryngeal reflex response. Atropine, when placed intrathecally, resulted in a significant reduction of apnea as well as a decrease in the cardiovascular changes that occur during the reflex 60 minutes following its injection. Edrophonium, when placed intrathecally, resulted in a significant prolongation of apnea as well as death by asystole in 2 animals during laryngeal stimulation. Atropine placed intravenously also resulted in a significant reduction of apnea length, but required greater than 180 minutes to do so.

Correlation between the Laryngeal Brain Stem Evoked Response and the Laryngeal Chemoreflex in the Porcine Model

The laryngeal brain stem evoked response (LBR) represents the neural activity involved in laryngeal reflex pathways. The laryngeal chemoreflex (LCR) is a centrally mediated response consisting of apnea and hemodynamic changes that result from laryngeal stimulation. The purpose of this study is to determine the characteristics of the LBR that are predictive of LCR severity in the porcine model. The duration of apnea resulting from stimulation of the supraglottic larynx defined LCR severity. The LBR tracings were recorded from electrodes flanking the brain stem following direct electrical stimulation of the superior laryngeal nerve. The LBR peak latencies from piglets demonstrating prolonged LCR apnea were compared to those without an exaggerated LCR response. Two LBR peak latencies demonstrated a statistically significant difference between the two piglet groups. These peak latencies appear to be indicators of susceptibility to exaggerated laryngeal reflex sensitivity. Thus, the LBR may prove useful in identifying and evaluating subjects predisposed to conditions associated with dysfunctional laryngeal reflex activity.

Arterial chemoreceptor influences on the laryngeal chemoreflex.

Prolonged apnea and cardiovascular changes have been elicited in infant animals by the application of water to the laryngeal mucosa. Previous reports have produced conflicting evidence in regard to the possible role of arterial chemoreceptors in modulating this reflex. The present study was designed to determine the effect of carotid body stimulation or suppression on the duration of apnea and severity of cardiovascular changes in response to water in the larynx of piglets. The role of swallowing in terminating the apnea was also investigated. Hypoxia and isoproterenol, both carotid body stimuli, caused decreased apnea duration. Hyperoxia was associated with prolonged apnea duration; however, dopamine, which inhibits carotid body chemoreceptors, produced no significant change. Hypotension and bradycardia were only observed after prolonged apnea or chemoreceptor stimulation, supporting the concept that the cardiovascular component of the laryngeal chemoreflex is a result of changes in blood gas concentration rather than a direct response to laryngeal chemostimulation. The interval between water application and initiation of swallowing was not significantly affected by hypoxia or carotid body stimulation and swallowing did not always occur before resumption of breathing.

Lidocaine effects on the laryngeal chemoreflex, mechanoreflex, and afferent electrical stimulation reflex.

The use of lidocaine hydrochloride as either a topical or intravenous agent has become a common practice for minimizing laryngospasm and the reflex cardiovascular effects resulting from upper airway manipulation. The efficacy and mechanism of action of lidocaine for this purpose remain unclear. We evaluated the effect of lidocaine on the laryngeal chemoreflex (LCR), mechanoreflex (LMR), and superior laryngeal nerve electrical stimulation adductor reflex (SLN-ESAR) in piglets. Cardiopulmonary responses were used to assess LCR and LMR. Latency following SLN stimulation was used to assess SLN-ESAR. Intravenous lidocaine hydrochloride at 3 mg/kg produced no suppression of the LCR, LMR, or latency (SLN-ESAR onset latency before lidocaine 11.7 +/- 0.7 milliseconds, after lidocaine 12.2 +/- 0.5 milliseconds; peak latency before lidocaine 13.2 +/- 0.2 milliseconds, after lidocaine 13.4 +/- 0.4 milliseconds). Topically applied lidocaine at the same dose eliminated both LCR and LMR responses in all animals, with return of reflex responses 15 minutes after application. No effect on the SLN-ESAR was seen with application of topical lidocaine. This study supports topical lidocaine as a suppressant of laryngeal mucosal neuroreceptors without central neural reflex effects. Intravenous lidocaine did not affect peripheral neuroreceptors, nor did it significantly affect the latency of the SLN-ESAR neural reflex arc. Intravenous and topical lidocaine differ in mechanism of action and efficacy with regard to modulation of reflex effects induced by laryngeal stimulation.

Laryngeal brainstem evoked response: A developmental study

A developmentally receding laryngeal chemoreflex (LCR) has been described in infant animals of several species characterized by vocal cord adduction in response to laryngeal stimulation as well as a potentially fatal cardio-respiratory response. Age-related differences in the brainstem respiratory centers may account for differences in the LCR and play a role in such disorders as Sudden Infant Death Syndrome (SIDS) and infant apnea. Study of the LCR at the brainstem level could provide insights into normal maturation of respiratory centers and eventually the pathophysiology of these disorders. The present study evaluated the laryngeal brainstem response (LBR) evoked by electrical stimulation of the superior laryngeal nerve in kittens using a far-field technique similar to auditory brainstem response testing. Recordings were obtained via posterior pharyngeal and posterior cervical recording sites and compared to results previously obtained in our laboratory for adult cats. The LBR in kittens demonstrated differences in threshold, latencies, and morphology which suggests that postnatal maturation of laryngeal function at the brainstem level does occur.

Hypoxia reinforces laryngeal reflex bradycardia in infants.

The laryngeal chemoreflex involves bradycardia, apnea, swallowing and peripheral vasoconstriction. This reflex was studied in twelve infants, aged 5 days-28 weeks, who had sustained an apparent life-threatening event or were siblings of infants who had died of the sudden infant death syndrome. The bradycardic and apneic components of the reflex were found to be significantly, and sometimes powerfully, reinforced when elicited by pharyngeal water instillation during acute, mild hypoxia (transcutaneous PO2 4.6-8.3 kPa). Apnea duration during normoxia was 0.7-15 sec, and during hypoxia 2-30 sec. Heart rate change ranged from +26% to -21% during normoxia, as compared with -4% to -63% during hypoxia. The percentage change in heart rate was found to inversely correlate with the transcutaneous PO2-level prevailing when the reflex was elicited. The conclusion is that there is a significant reinforcement of the cardiorespiratory adjustments when the laryngeal reflex is activated during simultaneous excitation of the peripheral arterial chemoreceptors. One infant, showing a particularly strong increase of the cardiorespiratory response to laryngeal receptor stimulation during hypoxia, later died of sudden infant death syndrome.

Motor drive and metabolic responses during repeated submaximal contractions in humans.

Contractile failure during various types of exercise has been attributed to intramuscular metabolic changes. We examined the temporal changes in force-generating capacity and metabolic state during intermittent isometric contractions in humans. One-legged quadriceps contractions at 30% maximum voluntary contraction (MVC) were executed for 6 s, with 4 s of rest between. The decrease in force-generating capacity was tested from brief MVC's and short bursts of 50-Hz stimulation applied at 5-min intervals. After 1 min of exercise, the MVC force declined linearly and in parallel to the 50-Hz stimulation force, indicating that the contractile failure was due to intramuscular processes. After 30 min of exercise the MVC force had declined by approximately 40% compared with the value obtained after 1 min. In separate experiments the same contraction protocol was followed, but two-legged contractions were used. Muscle biopsies taken after 5, 15, and 30 min of exercise showed only minor changes in the concentrations of glycogen, lactate, creatine phosphate (CrP), and ATP. However, at exhaustion, defined as loss of ability to sustain the target force, the concentrations of CrP and glycogen were reduced by 73 and 32%, and muscle lactate concentration had increased to 4.8 mmol/kg wet wt. Thus the gradual decline in force-generating capacity was not due to lactacidosis or lack of substrates for ATP resynthesis and must have resulted from excitation/contraction coupling failure, whereas exhaustion was closely related to phosphagen depletion, without significant lactacidosis.

Upper airway chemoreflex responses to saline and water in preterm infants

Laryngeal chemoreflex (LCR) responses elicited by fluid irrigation of the larynx have been described repeatedly in animals, whereas evidence for a similar reflex in human infants is extremely limited. Using nasopharyngeal catheters to instill small volumes of warm saline or water into the pharynx, we examined the incidence and characteristics of such a reflex in nine premature infants. Saline and water elicited the same pattern of responses, which frequently included swallows, central apnea, and airway obstruction and less commonly featured coughs, prolonged apnea, and arousal. With the exception of arousal, the incidence of these responses was significantly greater after delivery of water stimuli than after saline bolus administration. We therefore deduce chemoreceptor involvement in generation of these reflex responses and propose a laryngeal site for this sensory system, as in animals. Since greater potency of water compared with saline was demonstrable in all the infants studied, we further conclude that most preterm infants possess an upper airway chemoreflex.

Laryngeal chemoreflex: anatomic and physiologic study by use of the superior laryngeal nerve in the piglet.

The laryngeal chemoreflex (LCR) was investigated in 21 piglets (ages 6 to 80 days old) with the use of physiologic and histologic techniques. The central projection of the superior laryngeal nerve (SLN) was determined in 14 animals by use of horseradish peroxidase-wheat germ agglutinin. Ipsilateral labeling of the solitary tract nucleus was seen. The caudal extent of the labeling varied with age. Sensory labeling of the nucleus ambiguus was present bilaterally in three younger animals and unilaterally in older piglets. Bilateral labeling of the nucleus dorsomedialis was seen in all ages. Apneic and cardiovascular response to water stimulation of laryngeal mucosa and the laryngeal adductor reflex (LAR) were examined in 16 piglets. Blunting of the apneic and cardiovascular response was seen after sacrifice of a single SLN. Hypoxia did not significantly affect the LAR or apnea duration in animals with only one intact SLN. A contralateral LAR was found in younger animals. Relevance to the LCR is also discussed.

Dynamics of breathing in newborn mammals.

Dynamics of breathing in newborn mammals.

Effects of Carotid Body Maturation and Terbutaline on the Laryngeal Chemoreflex in Newborn Lambs

The response to laryngeal chemoreflex (LCR) water stimulation was compared in unanesthetized awake 4- to 10-day-old preterm and 2- to 4-wk-old term lambs before and after infusion of a beta-adrenergic agonist, terbutaline, given pre- and postcarotid body denervation (CBD). Ventilation decreased more in response to LCR stimulation post-CBD in the older lambs. CBD did not change the respiratory response to LCR stimulation in the younger lambs. LCR stimulation resulted in less bradycardia post-CBD in both groups. Terbutaline significantly attenuated the LCR response in the older lambs pre-CBD but not post-CBD. LCR respiratory response was not changed in the younger lambs when terbutaline was infused, pre- or post-CBD. Compared to wakefulness, the LCR response in preterm lambs was greater in sleep not associated with arousal. If arousal occurred, LCR response during sleep did not differ from that during wakefulness. The incidence of arousal decreased markedly after CBD, suggesting that arousal is modified by the carotid bodies. It is concluded that the carotid bodies modify the reflex response to LCR stimulation in 2- to 4-wk-old lambs. During the 1st postnatal wk, preterm lambs have a reduced carotid body function during wakefulness and, therefore, a decreased hypoxic ventilatory response and increased respiratory response to LCR stimulation. The attenuating effect of terbutaline on LCR response is partially related to mature carotid body function.