Laryngeal Chemoreflex Response Research Articles

The laryngeal chemoreflex: An evaluation of the normoxic response

The laryngeal chemoreflex is a reflexive central apnea, bradycardia, and cardiovascular collapse that occurs in young, maturing mammals in response to exposure of the laryngeal mucosa to acidic and/or organic stimuli. The severity of the laryngeal chemoreflex varies within a species from one animal to another, and in some animals, the response can be fatal. This study seeks to identify those factors that contribute to fatal laryngeal chemoreflex responses when the larynx is stimulated under normoxic conditions, and to define how the normoxic response differs from the hypoxic laryngeal chemoreflex response. This is a prospective study evaluating the response to laryngeal stimulation of 80 newborn piglets. The laryngeal chemoreflex response was elicited from 67 piglets under normoxic conditions. The data were collected from a combination of three separate experimental protocols, each of which included inducing the laryngeal chemoreflex under normoxic conditions as the first step. The physiologic response was recorded with a combination of arterial blood gas, pulse oximetry, blood pressure, and continuous cardiac monitoring. Resumption of respirations occurred when the pCO(2) rose by a mean of 8.34 (Standard Deviation [SD] = 4.8) mmHg, regardless of response severity (ANOVA, P > .05). Moderate (requiring supplemental O(2) for recovery) and profound (fatal) responders had a significantly higher prestimulation pCO(2) (95% confidence interval [CI] 39.8-44.8 mmHg and 40.5-46.4 mmHg, respectively) than did mild (recovery without assistance) responders (95% CI 36.8-40.8 mmHg, ANOVA, P < .05). Baseline pH was statistically significantly different as a function of response severity (95% CI profound: 7.29-7.37, moderate: 7.33-7.38, and mild 7.36-7.39, P < .05). Accumulation of arterial CO(2) is associated with resumption of respirations during the normoxic laryngeal chemoreflex. The combination of an elevated prestimulation pCO(2) and a low prestimulation pH predicts a profound laryngeal chemoreflex response under normoxic conditions.

Determinants of Fatal Apnea Responses to Acid Stimulation of the Larynx in Piglets

This study explores the physiological determinants of laryngeal chemoreflex (LCR) response severity under hypoxic conditions. Thirty-four piglets underwent hypoxic laryngeal stimulation. Physiologic data were collected, and responses were graded as mild, moderate, or profound. Prestimulation hypoxia caused respiratory depression and carbon dioxide retention in profound responders and respiratory stimulation in mild and moderate responders (p < .05). Resumption of respiration occurred in all animals when the PaCO2 rose by a mean +/- SD of 15.1 +/- 6.5 mm Hg (p > .05). There was a significant difference between mild, moderate, and severe responders in change in arterial PaO2 and hydrogenated hemoglobin saturation during the LCR-induced response (p < .001 for both). Resumption of respiration is associated with accumulation of arterial PaCO2. The respiratory response to hypoxia predicts the severity of the LCR response. The severity of the LCR-induced response is associated with changes in arterial PaO2 and hydrogenated hemoglobin saturation during the LCR-induced apnea.

Maturation and transformation of reflexes that protect the laryngeal airway from liquid aspiration from fetal to adult life

Several reflexes are initiated in the fetus and newborn when hypochloremic or strongly acidic solutions contact the epithelium that surrounds the entrance to the laryngeal airway. These reflexes, known collectively as the laryngeal chemoreflex (LCR), include startle, rapid swallowing, apnea, laryngeal constriction, hypertension, and bradycardia. Many studies have shown that prolonged apnea associated with the LCR may be life threatening and might conceivably be a cause of sudden infant death syndrome. This certainly may be true, but the concept of a lethal LCR paradoxically contrasts with the view that these several reflexes have an important airway-protective role. As the infant matures, rapid swallowing and apnea become much less pronounced, whereas cough and possibly laryngeal constriction become more prominent. This transformation is primarily related to central neural processing rather than to changes in the airway mucosal “water receptors” that initiate the reflex. The LCR develops in the fetus, in an all-aqueous environment, during a period in which aspiration of amniotic fluid poses a serious threat to life. This and other considerations suggest that the transformation in LCR responses from fetal to adult life can be viewed as functionally appropriate to their primary role in defending the airway from aspiration. The laryngeal “water receptors” that initiate the LCR in infants and adults alike appear to be the primary sensory mechanism for defending the airway from aspiration of liquids.

Effect of a second laryngeal stimulation during recovery from the laryngeal chemoreflex.

The laryngeal chemoreflex is a potential mechanism for sudden infant death. In experimental protocols in which a full recovery is allowed between stimuli, no laryngeal chemoreflex responses result in a fatal outcome. In the clinical situation there are no controls to prevent repeated laryngeal stimulation before a full recovery. The effect of a laryngeal stimulus applied during or soon after a laryngeal chemoreflex-induced apnea was investigated. Eighteen piglets were divided into groups aged 10 to 12 days, 17 to 21 days, and 32 to 36 days. Laryngeal stimulation was performed under normoxic conditions with water applied to the mucosa. Baseline respiratory and cardiovascular response data were measured. After recovery an initial stimulation was applied, followed by a second stimulation during the apnea or 5, 30, 60, or 120 seconds after restoration of breathing. No profound apneas occurred with baseline laryngeal stimulation. In piglets aged 32 to 36 and 17 to 21 days, a second laryngeal stimulus resulted in a shortened apnea duration. The response varied in piglets aged 10 to 12 days with profound apneas observed in 2 of 6 subjects and 4 of 30 trials. Piglets aged 17 to 36 days are less susceptible to the laryngeal chemoreflex during the immediate recovery period. In piglets aged 10 to 12 days, the laryngeal chemoreflex response may be more severe after a second stimulus.

Effect of a second laryngeal stimulation during recovery from the laryngeal chemoreflex

The laryngeal chemoreflex is a potential mechanism for sudden infant death. In experimental protocols in which a full recovery is allowed between stimuli, no laryngeal chemoreflex responses result in a fatal outcome. In the clinical situation there are no controls to prevent repeated laryngeal stimulation before a full recovery. The effect of a laryngeal stimulus applied during or soon after a laryngeal chemoreflex–induced apnea was investigated. Eighteen piglets were divided into groups aged 10 to 12 days, 17 to 21 days, and 32 to 36 days. Laryngeal stimulation was performed under normoxic conditions with water applied to the mucosa. Baseline respiratory and cardiovascular response data were measured. After recovery an initial stimulation was applied, followed by a second stimulation during the apnea or 5, 30, 60, or 120 seconds after restoration of breathing. No profound apneas occurred with baseline laryngeal stimulation. In piglets aged 32 to 36 and 17 to 21 days, a second laryngeal stimulus resulted in a shortened apnea duration. The response varied in piglets aged 10 to 12 days with profound apneas observed in 2 of 6 subjects and 4 of 30 trials. Piglets aged 17 to 36 days are less susceptible to the laryngeal chemoreflex during the immediate recovery period. In piglets aged 10 to 12 days, the laryngeal chemoreflex response may be more severe after a second stimulus. (Otolaryngol Head Neck Surg 1996;114:84-90.)

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.

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.

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.

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.

Effect of beta-adrenergic agonists on apnea reflexes in newborn lambs.

The laryngeal chemoreflex and the trigeminal diving reflex were studied in unanesthetized newborn lambs. Water stimulation of the laryngeal chemoreflex resulted in apnea, bradycardia, hypertension, and blood flow redistribution in the dive pattern. This response was significantly reduced after treatment with beta-adrenergic agonists, e.g., terbutaline. The response to laryngeal saline stimulation was not significantly altered by beta-adrenergic agonists. A similar response to trigeminal dive reflex stimulation elicited through cooling of the snout was also significantly reduced by terbutaline. Propranolol, a beta-adrenergic antagonist, reversed the terbutaline-induced effect on the laryngeal chemoreflex response. Stimulation of the superior laryngeal nerve resulted in a reflex response comparable to that from laryngeal water stimulation. The reflex response was also attenuated by terbutaline, which indicates that the action of terbutaline is not on the laryngeal chemoreceptors. A possible direct effect from beta-adrenergic agonists on the respiratory center is suggested by a latency of 15-30 min before the reflex response was reduced after intravenous but not intrathecal administration. An effect of terbutaline via the arterial chemoreceptors is also possible.

Laryngeal Chemoreflex in Newborn Lambs: Respiratory and Swallowing Response to Salts, Acids, and Sugars

The laryngeal chemoreflex was tested in a standardized manner in eighteen 1- to 6-day-old lambs. The respiratory and swallowing components of the reflex response to chemical solutions introduced to the larynx were quantified to characterize the function of the receptors and to elucidate what kind of receptors most likely are involved. A relationship between the strength of the stimulus and the respiratory response was found. The response was suppressed with the addition of small amounts of CaCl2, NaCl, and LiCl. NaCl, 0.3--0.6 M, 0.15 M NaCl titrated to a pH of 3--5 with hydrochloric or acetic acid, and 0.25--1.0 M glucose in 0.15 M NaCl elicited the reflex response. A quantitative separation was seen in the respiratory response to equimolar concentrations of the salt solutions as well as to the acid solutions in normal saline with equal pH. The response to glucose was significantly reduced after application of potassium gymnemate (P less than 0.001). A direct relationship between the amount of swallowing and the respiratory response was found (r = 0.83). The laryngeal chemoreflex responses to the stimuli used have certain functional characteristics that are similar to taste receptor responses. This would suggest that the taste bud-like structures present in the laryngeal area are likely receptors for mediation of the reflex.