Dysphagia as a Missing Link Between Post-surgical- and Opioid-Related Pneumonia.

PURPOSE: Postoperative pneumonia remains a common complication of surgery, despite increased attention. The purpose of our study was to determine the effects of routine surgery and post-surgical opioid administration on airway protection risk. METHODS: Eight healthy adult cats were evaluated to determine changes in airway protection status and for evidence of dysphagia in two experiments. (1) In four female cats, airway protection status was tracked following routine abdominal surgery (spay surgery) plus low-dose opioid administration (buprenorphine 0.015 mg/kg, IM, q8-12 h; n = 5). (2) Using a cross-over design, four naive cats (2 male, 2 female) were treated with moderate-dose (0.02 mg/kg) or high-dose (0.04 mg/kg) buprenorphine (IM, q8-12 h; n = 5). RESULTS: Airway protection was significantly affected in both experiments, but the most severe deficits occurred post-surgically as 75% of the animals exhibited silent aspiration. CONCLUSION: Oropharyngeal swallow is impaired by the partial mu-opioid receptor agonist buprenorphine, most remarkably in the postoperative setting. These findings have implications for the prevention and management of aspiration pneumonia in vulnerable populations.

Serotonin therapies for opioid-induced disordered swallow and respiratory depression.

Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We tested the effects of the clinically relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated the utility of 5-HT1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague-Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus, and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing. We evaluated the hypotheses that swallowing varies by stimulus, opioids depress swallowing and breathing, and that 5-HT1A agonists improve these depressions. Our results largely confirmed the following hypotheses: 1) swallow-related EMG activity was larger during swallows elicited by esophageal distension plus oral water infusion than by either stimulus alone. 2) Buprenorphine depressed swallow in both sexes, but females were more susceptible to total swallow suppression. 3) Female animals were also more vulnerable to opioid-induced respiratory depression. 4) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pretreatment with the partial 5-HT1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5) 8-OH-DPAT enhanced mylohyoid and thyropharyngeus EMG amplitude during swallow but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide preclinical evidence of a 5HT1A agonist for the treatment of respiratory depression and dysphagia.NEW & NOTEWORTHY This is the first study, to our knowledge, to evaluate sex-specific effects of opioid administration on pharyngeal swallow. We expand on a small but growing number of studies that report a lower threshold for opioid-induced respiratory depression in females compared with males, and we are the first to produce this effect with the partial µ-opioid-receptor agonist buprenorphine. This is the first demonstration, to our knowledge, that activation of 5-HT1A receptors can improve swallow and breathing outcomes following systemic buprenorphine administration.

Serotonin therapies for opioid-induced dysphagia and respiratory depression: sex differences in a rat electromyography model.

Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We sought to test the effects of the clinically-relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated utility of serotonin 5-HT1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing outcomes following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing behaviors. We evaluated the hypotheses that swallow varies by stimulus, opioids depress swallow and breathing, and that 5-HT1A agonists improve these depressions. Our results largely confirmed the hypotheses: 1) Swallow-related muscle activity was larger during swallows elicited by oral water infusion plus esophageal distension than by either stimulus alone. 2) Buprenorphine depressed swallow in both sexes, but most significantly in females. 3) Female animals were more susceptible to buprenorphine-induced respiratory arrest. 4) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pre-treatment with the partial 5-HT1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5) 8-OH-DPAT enhanced swallow-related mylohyoid drive, but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide pre-clinical evidence of a 5HT1A agonist for the treatment of respiratory depression and dysphagia.

Laryngeal and swallow dysregulation following acute cervical spinal cord injury.

Laryngeal function is vital to airway protection. Although swallow is mediated by the brainstem, the mechanism underlying the increased risk of dysphagia after cervical spinal cord injury (SCI) is unknown. We hypothesized that: 1) loss of descending phrenic drive affects swallow and breathing differently, and 2) loss of ascending spinal afferent information alters swallow regulation. We recorded electromyograms (EMGs) from upper airway and chest wall muscles in freely breathing pentobarbital-anesthetized cats and rats. Laryngeal abductor activity during inspiration increased about twofold following C2 lateral hemisection. Ipsilateral to the injury, the crural diaphragm EMG amplitude was reduced during breathing (62 ± 25% change postinjury), but no animal had complete termination of activity; 75% of animals had increased contralateral diaphragm recruitment, but this did not reach significance. During swallow, laryngeal adductor and pharyngeal constrictor muscles increased activity, and diaphragm activity was bilaterally suppressed. This was unexpected because of the ipsilateral-specific response during breathing. Swallow-breathing coordination was disrupted by injury, and more swallows occurred during early expiration. Finally, to determine if the chest wall is a major source of feedback for laryngeal regulation, we performed T1 total transections in rats. As in the C2 lateral hemisection, inspiratory laryngeal recruitment was the first feature noted after injury. In contrast to the C2 lateral hemisection, diaphragmatic drive increased after T1 transection. Overall, we found that SCI alters laryngeal drive during swallow and breathing, and alters swallow-related diaphragm activity. Our results show behavior-specific effects, suggesting that swallow is affected more than breathing is by SCI, and emphasizing the need for additional studies on the effect of ascending afferents from the spinal cord on laryngeal function.NEW & NOTEWORTHY This is the first manuscript to determine the impact of cSCI on laryngeal and swallow function, and to describe a possible mechanism for dysphagia and altered airway protection after injury.

Rapid activation of esophageal mechanoreceptors alters the pharyngeal phase of swallow: Evidence for inspiratory activity during swallow.

Swallow is a complex behavior that consists of three coordinated phases: oral, pharyngeal, and esophageal. Esophageal distension (EDist) has been shown to elicit pharyngeal swallow, but the physiologic characteristics of EDist-induced pharyngeal swallow have not been specifically described. We examined the effect of rapid EDist on oropharyngeal swallow, with and without an oral water stimulus, in spontaneously breathing, sodium pentobarbital anesthetized cats (n = 5). Electromyograms (EMGs) of activity of 8 muscles were used to evaluate swallow: mylohyoid (MyHy), geniohyoid (GeHy), thyrohyoid (ThHy), thyropharyngeus (ThPh), thyroarytenoid (ThAr), cricopharyngeus (upper esophageal sphincter: UES), parasternal (PS), and costal diaphragm (Dia). Swallow was defined as quiescence of the UES with overlapping upper airway activity, and it was analyzed across three stimulus conditions: 1) oropharyngeal water infusion only, 2) rapid esophageal distension (EDist) only, and 3) combined stimuli. Results show a significant effect of stimulus condition on swallow EMG amplitude of the mylohyoid, geniohyoid, thyroarytenoid, diaphragm, and UES muscles. Collectively, we found that, compared to rapid cervical esophageal distension alone, the stimulus condition of rapid distension combined with water infusion is correlated with increased laryngeal adductor and diaphragm swallow-related EMG activity (schluckatmung), and post-swallow UES recruitment. We hypothesize that these effects of upper esophageal distension activate the brainstem swallow network, and function to protect the airway through initiation and/or modulation of a pharyngeal swallow response.