Chemoradiation to the submental muscles alters hyoid movement during swallowing in a rat model.

Hyolaryngeal dysfunction is a commonly reported swallowing problem after chemoradiation treatment for head and neck cancer. The displacement of the hyolaryngeal complex during swallowing protects the airway and assists in opening the upper esophageal sphincter. Activation of the submental muscles, specifically the mylohyoid and geniohyoid muscles, is thought to facilitate movement of the hyoid. The purpose of this study was to determine if targeted radiation to the submental muscles given concurrently with chemotherapy alters hyolaryngeal displacement 1 mo after treatment. We hypothesized that chemoradiation treatment would result in abnormal patterns of hyoid movement compared with controls. Furthermore, we propose that these changes are associated with alterations in bolus size and discoordination of the jaw during drinking. Eighteen rats underwent either chemoradiation, radiation, or no treatment. Radiation treatment was targeted to submental muscles using a clinical linear accelerator given in 12 fractions of 4 Gy (3 days per week). Cycles of 1 mg/kg of cisplatin were administered concurrently each week of radiation. One month posttreatment, videofluoroscopy swallow studies (VFSS) were performed in self-drinking rats using a fluoroscope customized with a high-speed camera. The hyoid, jaw, and hard palate were tracked during swallowing from VFSS. Hyoid kinematics were analyzed from the start to the end of hyoid movement, and parameters were compared with bolus size and jaw movement. Significant differences in hyoid retraction parameters were found postchemoradiation. Alterations in the trajectory of hyoid motion during swallowing were observed. The findings demonstrate early changes in hyoid motion during swallowing associated with chemoradiation treatment.NEW & NOTEWORTHY Chemoradiation treatment for head and neck cancer can cause functional impairments in swallowing, which can adversely affect quality of life. This study provides new evidence that chemoradiation targeted to the submental muscles provokes early adaptations in hyoid movement during swallowing, which correlate with changes in bolus size. We also demonstrate a method for tracking the hyoid during swallowing in a rat model of chemoradiation injury.

Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment.

BACKGROUND: 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality. METHODS: Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12 months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). RESULTS: Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline. CONCLUSIONS: The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.

Impacto do tratamento medicamentoso na voz, fala e deglutição de pacientes com esclerose lateral amiotrófica: revisão sistemática / Impact of drug treatment on voice, speech, and swallowing in patients with amyotrophic lateral sclerosis: a systematic review

RESUMO Objetivos Revisar sistematicamente a literatura sobre o impacto do tratamento medicamentoso nas funções de voz, fala e deglutição de indivíduos adultos com esclerose lateral amiotrófica esporádica, mensuradas por meio de escalas e seus respectivos escores, em relação ao grupo placebo. Estratégia de pesquisa A busca foi realizada com base na estratégia PICO (problema/população/paciente; intervenção; comparação/controle; desfecho/outcome). As palavras-chave foram selecionadas a partir de consulta aos Descritores em Ciências da Saúde (DeCS) e ao Medical Subject Headings (MeSH). Dois pesquisadores independentes fizeram busca na American Speech-Language-Hearing Association (ASHA), Cochrane, LILACS, PubMed, Scopus e Web of Science, em inglês, espanhol e português. Critérios de seleção Foram incluídos ensaios clínicos randomizados, realizados em adultos, e excluídos artigos cujos desfechos estavam relacionados à autoavaliação e à qualidade de vida, teses, dissertações, apenas resumos disponíveis, estudos de caso, estudos experimentais, capítulos de livro, enciclopédias e comunicações breves. Os estudos foram avaliados por meio das ferramentas Robins II (Risk Of Bias In Non-randomized Studies II) e GRADE (Grading of Recommendations Assessment, Development and Evaluation). Resultados dos 9824 artigos encontrados, 5 realizaram a intervenção medicamentosa e foram selecionados para análise. Observou-se ausência de estudos voltados para reabilitação das funções bulbares. A qualidade de evidência gerada variou de alto a baixo risco e o nível de evidência, de baixo a muito baixo. Conclusão a maioria dos estudos demonstra que o tratamento medicamentoso atrasa a degeneração das funções bulbares, com relação ao placebo, embora tal achado não tenha sido observado nos escores de escalas que mensuram tais funções. Os estudos apresentam risco de viés de seleção e muito baixa/baixa qualidade metodológica, limitando a confiança nos achados.

ABSTRACT Purpose To carry out a systematic review of the literature on the impact of drug treatment on the voice, speech, and swallowing functions of adult individuals with sporadic ALS, measured through scales and their respective scores, concerning the placebo group. Research strategy The search strategy was created based on the PICO strategy. The keywords were selected from a consultation with the health sciences descriptors - DECS and the medical subject headings - MeSH. Two independent researchers searched ASHA, Cochrane, Lilacs, Pubmed, Scopus and Web of Science, in English, Spanish and Portuguese. Selection criteria Randomized clinical trials, carried out on adults, were included, and articles with outcomes related to selfassessment and quality of life, theses, dissertations, abstracts only , case studies, experimental studies, book chapters, encyclopedia and brief communication were excluded. The studies were evaluated using the Robins II and Grade tool. Results Of the 9824 articles found, 5 were selected for analysis and underwent drug intervention. It is noticed the absence of studies aimed at the rehabilitation of bulb functions. The quality of evidence generated varied from high to low risk and the level of evidence low and very low. Conclusion Most studies show a delay in the degeneration of bulbar functions in relation to placebo, although this finding has not been observed in the scores of scales that measure such functions. Studies are at risk of selection bias and very low/low methodological quality makes the findings questionable.

Prediction of Speech, Swallowing, and Quality of Life in Oral Cavity Cancer Patients: A Pilot Study.

OBJECTIVES/HYPOTHESIS: To investigate the impact of specific treatment-related variables on functional and quality of life outcomes in oral cavity cancer (OCC) patients. STUDY DESIGN: Retrospective Cohort. METHODS: Patients with primary OCC at least 6 months after resection and adjuvant therapy were included. Patients completed surveys including the Speech Handicap Index (SHI), M.D. Anderson Dysphagia Inventory (MDADI), and Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN). Performance Status Scale (PSS) and tongue mobility scale were completed to allow provider-rated assessment of speech and tongue mobility, respectively. Additional details regarding treatment were also collected. These data were used to generate a predictive model using linear regression. RESULTS: Fifty-three patients with oral tongue and/or floor of mouth (FOM) resection were included in our study. In multivariable analysis, greater postoperative tongue range of motion (ROM) and time since treatment improved SHI. Flap reconstruction and greater postoperative tongue ROM increased MDADI and PSS (eating and speech). A larger volume of resected tissue was inversely correlated with PSS (diet and speech). Tumor site was an important predictor of PSS (all sections). There were no statistically significant predictors of FACT-HN. CONCLUSIONS: In this pilot study, we propose a battery of tools to assess function in OCC patients treated with surgery. Using the battery of tools we propose, our results show that a surgical endpoint that preserves tongue mobility and employs flap reconstruction resulted in better outcomes, whereas those with greater volume of tissue resected and FOM involvement resulted in poorer outcomes. Larger prospective studies are needed to validate our findings. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2497-2504, 2021.

Effect of Capsaicinoids on Neurophysiological, Biochemical, and Mechanical Parameters of Swallowing Function.

Oropharyngeal dysphagia is prevalent in age-related neurological disorders presenting with impaired efficacy and safety of swallowing due to a loss of muscle force and sensory deficits. Stimulating the oropharynx with capsaicin that mediates Substance P release is an emerging pharmacological treatment option which needs further scientific evidence. Our aim was to comprehensively evaluate the effect of capsaicin on biochemical, neurophysiological, and biomechanical parameters of swallowing function. In a randomized study on healthy individuals, the impact of orally administered capsaicinoids at different dosages and application durations in comparison to non-carbonated water was evaluated. Time course and magnitude of salivary Substance P increase were monitored. Magnetoencephalography was used to detect cortical swallowing network alterations. Modifications in swallowing biomechanics were measured applying high-resolution pharyngeal manometry. Capsaicinoids at 10 µmol/L improved swallowing efficacy as seen by a significant increase of pharyngeal contractile integral and upper esophageal sphincter activation and relaxation times in manometry. Significant improvement of precision in a challenging swallow task accompanied by a reduction in swallowing-related submental electromyographic power was observed with capsaicinoids preconditioning at 10 µmol/L over 5 min, but not with continuous stimulation. The cortical activation pattern remained unchanged after any intervention. A significant increase of salivary Substance P was not detected with 10 µmol/L but with 50 µmol/L and lasted for 15 min after application. Capsaicinoids mediate dose-dependent Substance P release and positively alter swallowing biomechanics in healthy subjects. The results provide supportive evidence for the value of natural capsaicinoids to improve swallowing function.

Inflammatory Effects of Thickened Water on the Lungs in a Murine Model of Recurrent Aspiration.

OBJECTIVE: Liquid thickeners are commonly recommended in individuals with dysphagia and recurrent aspiration as a strategy for pneumonia prevention. The goal of this study was to examine the effects of small amounts of aspirated liquid thickener on the lungs. STUDY DESIGN: Animal model. Prospective small animal clinical trial. METHODS: Adult Sprague Dawley rats (n = 19) were divided into two groups and underwent three intratracheal instillations of either xanthan gum-based nectar-thick water (0.1-0.25 mL/kg) or water-only control over the course of 8 days. Blood was collected from a peripheral vein on days 1 and 8 and submitted for complete blood count (CBC) analysis. Rats were euthanized 10 days after the last instillation, and the lungs were harvested. Histopathology was conducted on lung specimens by a blinded licensed veterinary pathologist and scored for evidence of lung injury and pneumonia. RESULTS: Fifteen animals (8 nectar-thickener group, 7 control group) survived until the endpoint of the study (day 18). Serum CBC did not show abnormalities at any timepoint in either group. Histological evidence of lung inflammation and edema were significantly greater in the nectar-thick group compared to controls (P < .05). Signs of inflammation included aggregates of foamy macrophages, expansion of bronchiolar lymphoid tissue, and large numbers of eosinophilic intraalveolar crystals. Histiocytic and neutrophilic pneumonia was noted in one animal that received thickened liquids. CONCLUSION: Recurrent aspiration of small amounts of thickened water resulted in significant pulmonary inflammation in a murine model of aspiration. Results of this study support the need for further investigation of liquid thickener safety and its efficacy in reducing the pulmonary complications of swallowing disorders. LEVEL OF EVIDENCE: NA Laryngoscope, 131:1223-1228, 2021.

Effect of Topical Steroid on Swallowing Following ACDF: Results of a Prospective Double-Blind Randomized Control Trial.

STUDY DESIGN: Randomized, double-blinded, controlled trial. OBJECTIVE: To investigate the effectiveness of local intraoperative corticosteroids at decreasing the severity of swallowing difficulty following multilevel anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Dysphagia is a common complication after ACDF, and while for most patients the symptoms are mild and transient, some patients can suffer from severe dysphagia resulting in significant postoperative morbidity. Previous studies investigating the local application of corticosteroids are limited. METHODS: This was a prospective, randomized, double-blinded, controlled trial of patients undergoing 2, 3, or 4 level ACDF for radiculopathy and/or myelopathy. Patients undergoing multilevel ACDF were randomized to receive local corticosteroid in the retropharyngeal space or placebo (no steroid). Dysphagia was assessed using validated outcomes including the Eating Assessment Tool-10 (Eat-10) and Swallowing Quality of Life (SWAL-QOL) Questionnaire both preoperatively and at 1 day (POD1), 2 days (POD2), and 1-month postoperatively. RESULTS: One-hundred nine patients had a complete dataset available for analysis. Eat-10 scores were significantly lower in the Steroid group on POD2 (8 vs. 16, P = 0.03) and 1-month postoperatively (2 vs. 5, P = 0.03). A comparison of the individual SWAL-QOL subscale scores demonstrated that patients in the Steroid group had better scores than the Control group in various subscales at all postoperative time points. Significant differences were noted (always in favor of the Steroid group) in 40% of subscales on POD1, 60% of subscales on POD2, and 50% of subscales at 1-month postoperatively. The Control group never had a better SWAL-QOL subscale score at any time point postoperatively. CONCLUSION: Local administration of corticosteroid after multilevel ACDF can decrease postoperative severity and symptomatology of dysphagia during the immediate postoperative period to 1-month postoperatively. The long-term effects of local steroid administration on fusion and other complications will need to be established in future studies.Level of Evidence: 1.

Influences of GABAergic Inhibition in the Dorsal Medulla on Contralateral Swallowing Neurons in Rats.

OBJECTIVES: We aimed to examine the effect of unilateral inhibition of the medullary dorsal swallowing networks on the activities of swallowing-related cranial motor nerves and swallowing interneurons. METHODS: In 25 juvenile rats, we recorded bilateral vagal nerve activity (VNA) as well as unilateral phrenic and hypoglossal activity (HNA) during fictive swallowing elicited by electrical stimulation of the superior laryngeal nerve during control and following microinjection of the GABA agonist muscimol into the caudal dorsal medulla oblongata in a perfused brainstem preparation. In 20 animals, swallowing interneurons contralateral to the muscimol injection side were simultaneously recorded extracellularly and their firing rates were analyzed during swallowing. RESULTS: Integrated VNA and HNA to the injection side decreased to 49.0 ± 16.6% and 32.3 ± 17.9%, respectively. However, the VNA on the uninjected side showed little change after muscimol injection. Following local inhibition, 11 out of 20 contralateral swallowing interneurons showed either increased or decreased of their respective firing discharge during evoked-swallowing, while no significant changes in activity were observed in the remaining nine neurons. CONCLUSION: The neuronal networks underlying the swallowing pattern generation in the dorsal medulla mediate the ipsilateral motor outputs and modulate the contralateral activity of swallowing interneurons, suggesting that the bilateral coordination of the swallowing central pattern generator regulates the spatiotemporal organization of pharyngeal swallowing movements. LEVEL OF EVIDENCE: NA Laryngoscope, 131:2187-2198, 2021.

Cricopharyngeal bar and dermatomyositis: A cause of rapidly progressive dysphagia.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are immune-mediated conditions that affect striated muscle, and are frequently associated with dysphagia. Dysphagia in these cases can be due to weakness of the muscles involved in swallowing or the presence of restrictive pharyngeal defects, such as cricopharyngeal bars. Treatment of dysphagia in IIM revolves around immunosuppressive therapies, and procedures to disrupt cricopharyngeus muscle when immunosuppressive therapies are unsuccessful. CASE REPORT: A 73-year-old female presented with rapidly progressive proximal muscle weakness and dysphagia to the point she could not swallow liquids or solids. She had a rash over the extensor surfaces of the limbs, and periorbital-edema. Her creatine kinase was elevated, and skin biopsy showed an interface inflammatory reaction; however, myositis line assay revealed no autoantibodies, and a muscle biopsy was unremarkable. She was diagnosed with dermatomyositis with life-threatening dysphagia, and was admitted to our institution and treated with corticosteroids, methotrexate and intravenous immunoglobulin. A videofluoroscopic swallowing study revealed a large esophageal protrusion at the level of C5-C6, which was thought to be consistent with a cricopharyngeal bar, with large boluses unable to pass, leading to aspiration. After 10 weeks of treatment, the cricopharyngeal bar remained present, but swallowing had improved to the point that she was successfully swallowing all consistencies. CONCLUSION: Dysphagia associated with IIM can be multifactorial, and can be due to the involvement of the muscles of swallowing in the inflammatory process, or due to restrictive pharyngeal defects, and determination of the cause of dysphagia can assist with management.

Involvement of capsaicin-sensitive nerves in the initiation of swallowing evoked by carbonated water in anesthetized rats.

Capsaicin powerfully evokes the swallowing reflex and is a known therapeutic agent for improving dysphagia and preventing aspiration pneumonia. However, the role of capsaicin-sensitive nerves in the initiation of swallowing evoked by various natural stimuli remains unclear. To explore this question, we blocked laryngeal capsaicin-sensitive nerves following the coapplication of QX-314 and capsaicin (QX/Cap), and investigated the effects on swallowing evoked by mechanical and chemical stimulation in anesthetized rats. Swallows were evoked by capsaicin, carbonated water (CW), distilled water (DW), and punctate mechanical stimulation using von Frey filaments applied topically to the larynx. Swallows were documented by recording electromyographic activation of the suprahyoid and thyrohyoid muscles. The initiation of swallowing by capsaicin was strongly suppressed at 5 min following QX/Cap treatment and returned in a time-dependent manner. CW-evoked swallows at 5 min following QX/Cap treatment were significantly diminished compared with before and 30 min after treatment. In contrast, DW-evoked and mechanically evoked swallows were unchanged by QX/Cap treatment. Furthermore, CW-evoked swallows were virtually abolished by transection of the superior laryngeal nerves and significantly decreased by the topical application of acid-sensing ion channel-3 (ASIC3) inhibitor APETx2, but they were not affected by the nonselective transient receptor potential channel inhibitor ruthenium red or the ASIC1 inhibitor mambalgin-1. Taken together, we speculate that capsaicin-sensitive nerves play an important role in the initiation of CW-evoked swallows.NEW & NOTEWORTHY The initiation of swallowing evoked by laryngeal capsaicin and carbonated water application was diminished by the coapplication of QX-314 and capsaicin. Carbonated water-evoked swallows were also abolished by transection of the superior laryngeal nerves and were inhibited by the acid-sensing ion channel-3 inhibitor. Capsaicin-sensitive nerves are involved in the initiation of carbonated water-evoked swallows.

Safe, swallowable and palatable paediatric mini-tablet formulations for a WHO model list of essential medicines for children compound - A promising starting point for future PUMA applications.

More than 10 years after the Paediatric Regulation came into place there is still a strong need for paediatric medicines for off-patent drug substances. Numerous compounds for which a paediatric formulation does not exist can be found on the WHO Model List of Essential Medicines for Children and in the EMA Inventory of the Needs for Paediatric Medicines. Many of these compounds are off patent, which offers the opportunity for obtaining marketing authorisations for paediatric use. The present study focused on the development of paediatric immediate-release mini-tablet formulations for furosemide. Essential formulation criteria included the use of excipients that are regarded as safe for children, the ease of manufacturing, a high dose flexibility, fast disintegration, a robust drug release and a good acceptability. Only excipients regarded as safe for use in children were used in formulation screening. Compressibility, tablet hardness, disintegration and palatability were the main screening parameters. Formulations with a hardness of  > 20 N, a disintegration time < 3 min (fast disintegration) and a good palatability were selected for mini-tablet production. Based on this pre-assessment two mini-tablet formulations with a furosemide drug load of 2.5 mg were developed. Both were easy to manufacture, had an appropriate hardness, a short disintegration time and met pharmacopoeial requirements with regard to content uniformity and physical testing. Biorelevant in vitro dissolution experiments mimicking different modes (with water or dosing vehicles) of administering age-appropriate furosemide doses to children of different age groups indicated a fast and robust drug release. Overall, the novel mini-tablet formulations present with an increased dose flexibility, excipient safety, swallowability and palatability and are thus a promising starting point for the development of solid oral dosage forms for drugs with paediatric therapeutic needs.

Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1.

Importance: Niemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, a drug used off-label in the United States for the treatment of NPC1, appears to stabilize neurologic disease progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia and aspiration risk has not been demonstrated instrumentally. Objective: To determine if miglustat therapy is associated with stabilized swallowing dysfunction in individuals with NPC1. Design, Setting, and Participants: Patients with confirmed NPC1 diagnoses were evaluated in a single-center cohort study of NPC1 from April 1997 to November 2019. Longitudinal data from individuals with neurologic disease onset prior to age 15 years were analyzed. The study population was divided into those with neurologic disease onset in early childhood (age <6 years) and late childhood (age ≥6 years and <15 years). Analysis began September 2019. Exposures: Oral miglustat at baseline and at follow-up. Main Outcomes and Measures: Oropharyngeal swallowing function was assessed with videofluoroscopic swallowing studies. Overall swallowing ability and aspiration risk were evaluated using the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain and an adapted Rosenbek aspiration-penetration scale, respectively. Results: Overall, 50 participants were evaluated at baseline (median [interquartile range] age, 9.4 [3.4-16.4] years; 26 [52%] female). The median (interquartile range) duration of follow-up was 3.0 (1.1-4.4) years. Miglustat use was associated with decreased odds of worse American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain outcomes in all 3 subsets (overall: odds ratio [OR], 0.09 [95% CI, 0.02-0.36); P < .001; early childhood: OR, 0.17 [95% CI, 0.04-0.67]; P = .01; late childhood: OR, 0.05 [95% CI, 0.01-0.29]; P = .001). Miglustat use was associated with decreased odds of worse Rosenbek aspiration-penetration scale outcomes in the overall cohort (OR, 0.28 [95% CI, 0.08-0.95]; P = .04) but not in each subgroup (early childhood: OR, 0.27 [95% CI, 0.06-1.22]; P = .09; late childhood: OR, 0.38 [95% CI, 0.06-2.33]; P = .29). Conclusions and Relevance: These data suggest that miglustat use is associated with stabilized swallowing function and reduced aspiration risk in NPC1, thus supporting its use in this population. In addition, these data demonstrate that a quantification of swallowing dysfunction can be used as a clinically relevant, functional outcome measure in future therapeutic trials in NPC1.

Sustained laryngeal transient receptor potential vanilloid 1 activation inhibits mechanically induced swallowing in anesthetized rats.

A major component of gastric acid is hydrochloric acid (HCl), which can activate transient receptor potential vanilloid 1 (TRPV1). In the present study, we investigated how sustained laryngeal TRPV1 activation affects the frequency of the swallowing reflex. Experiments were carried out on 85 male Sprague-Dawley rats. The effects of short and sustained application of chemicals (3 µl of 0.1 N HCl or capsaicin) on the frequency of swallowing and on time-dependent changes in the occurrence of swallowing evoked by supralaryngeal nerve stimulation were determined. To evaluate vascular permeability of the larynx, Evans blue dye was intravenously injected after 5 or 60 min of sustained TRPV1 activation. SB366791 (a TRPV1 inhibitor) and Cap/QX-314 (a TRPV1-expressed neuronal inhibitor) significantly inhibited HCl/capsaicin-induced swallowing, but air flow-induced swallowing was not affected. Although the number of air flow-induced swallows followed by capsaicin stimulation was not affected within 5 min, it was significantly reduced by 60-min capsaicin or HCl application. The swallowing threshold associated with supralaryngeal nerve stimulation did not significantly change throughout the recording period. Evans blue dye concentrations in the larynx were significantly higher at 60 min in the 10-5 M capsaicin group than in the control group. Our results suggest that sustained TPRV1 activation not only desensitizes TRPV1 but also inactivates mechanoreceptors, which may be attributed to increases in vascular permeability and edema, as part of an inflammatory process.NEW & NOTEWORTHY Although a transient receptor potential vanilloid 1 (TRPV1) inhibitor or TRPV1-expressed neuronal inhibitor significantly inhibited HCl/capsaicin-evoked swallowing, air flow-induced swallowing was not affected. The number of air flow-induced swallows was significantly reduced within 60 min of TRPV1 activation. Evans blue dye concentration in the larynx increased 60 min after capsaicin application. TPRV1 activation not only desensitizes TRPV1 but also inactivates mechanoreceptors caused by increases in vascular permeability and edema.

Opioids Interfere With Deglutitive Inhibition Assessed by Response to Multiple Rapid Swallows During High-Resolution Esophageal Manometry.

INTRODUCTION: Normal response to multiple rapid swallows (MRS) during high-resolution esophageal manometry is deglutitive inhibition; opioids may interfere with this. The aim of this study was to evaluate the response to MRS in patients on opioids, not on opioids, and healthy controls. METHODS: Response to MRS was evaluated for complete vs impaired inhibition in 72 chronic opioid users, 100 patients not on opioids, and 24 healthy controls. RESULTS: Impaired deglutitive inhibition was significantly more frequent in chronic opioid users compared with patients not on opioids and healthy controls (54% vs 14% vs 0%; P < 0.0001). DISCUSSION: Impaired deglutitive inhibition during MRS is frequent in opioid users, supporting that opioids interfere with esophageal inhibitory signals.

Quipazine Elicits Swallowing in the Arterially Perfused Rat Preparation: A Role for Medullary Raphe Nuclei?

Pharmacological neuromodulation of swallowing may represent a promising therapeutic option to treat dysphagia. Previous studies suggested a serotonergic control of swallowing, but mechanisms remain poorly understood. Here, we investigated the effects of the serotonergic agonist quipazine on swallowing, using the arterially perfused working heart-brainstem (in situ) preparation in rats. Systemic injection of quipazine produced single swallows with motor patterns and swallow-breathing coordination similar to spontaneous swallows, and increased swallow rate with moderate changes in cardiorespiratory functions. Methysergide, a 5-HT2 receptor antagonist, blocked the excitatory effect of quipazine on swallowing, but had no effect on spontaneous swallow rate. Microinjections of quipazine in the nucleus of the solitary tract were without effect. In contrast, similar injections in caudal medullary raphe nuclei increased swallow rate without changes in cardiorespiratory parameters. Thus, quipazine may exert an excitatory effect on raphe neurons via stimulation of 5-HT2A receptors, leading to increased excitability of the swallowing network. In conclusion, we suggest that pharmacological stimulation of swallowing by quipazine in situ represents a valuable model for experimental studies. This work paves the way for future investigations on brainstem serotonergic modulation, and further identification of neural populations and mechanisms involved in swallowing and/or swallow-breathing interaction.

The Effects of Mutual Interaction of Orexin-A and Glucagon-Like Peptide-1 on Reflex Swallowing Induced by SLN Afferents in Rats.

(1) Background: Our previous studies revealed that orexin-A, an appetite-increasing peptide, suppressed reflex swallowing via the commissural part of the nucleus tractus solitarius (cNTS), and that glucagon-like peptide-1 (GLP-1), an appetite-reducing peptide, also suppressed reflex swallowing via the medial nucleus of the NTS (mNTS). In this study, we examined the mutual interaction between orexin-A and GLP-1 in reflex swallowing. (2) Methods: Sprague-Dawley rats under urethane-chloralose anesthesia were used. Swallowing was induced by electrical stimulation of the superior laryngeal nerve (SLN) and was identified by the electromyographic (EMG) signals obtained from the mylohyoid muscle. (3) Results: The injection of GLP-1 (20 pmol) into the mNTS reduced the swallowing frequency and extended the latency of the first swallow. These suppressive effects of GLP-1 were not observed after the fourth ventricular administration of orexin-A. After the injection of an orexin-1 receptor antagonist (SB334867) into the cNTS, an ineffective dose of GLP-1 (6 pmol) into the mNTS suppressed reflex swallowing. Similarly, the suppressive effects of orexin-A (1 nmol) were not observed after the injection of GLP-1 (6 pmol) into the mNTS. After the administration of a GLP-1 receptor antagonist (exendin-4(5-39)), an ineffective dose of orexin-A (0.3 nmol) suppressed reflex swallowing. (4) Conclusions: The presence of reciprocal inhibitory connections between GLP-1 receptive neurons and orexin-A receptive neurons in the NTS was strongly suggested.

Sensory aspects of acceptability of bitter-flavoured 7.5 mm film-coated tablets in adults, preschool and school children.

There is great interest in demonstrating acceptability of solid oral formulations in paediatric populations. This study investigated the acceptability of small, 7.5 mm, bitter-flavoured, coated tablets in healthy children and adults. A randomised, double-blind acceptability test was performed involving 101 children (4-12 years) and 52 adults (18-75 years). Acceptability was measured by participants as sensory assessment of taste, mouthfeel and hedonic perception, and by researcher observations of ability to swallow the tablet and negative facial expressions. Additionally, the taste-masking effect of film coatings was assessed based on the intensity of bitterness perception. At least one tablet was voluntarily swallowed by 35.7% of 4-6-year olds, 74% of 7-12-year olds and 98% of adults. The bitterness of the tablet did not affect participants' ability to swallow it. The sensory properties determined whether the tablet was acceptable. The following factors: low bitterness, high smoothness, high slipperiness and pleasant aftertaste had a positive impact on overall palatability in both populations. The paediatric scores during sensory evaluation of tablets differed from adults, showing lower acceptability. This study demonstrates the multifactorial nature of palatability of tablets and highlights that adults' palatability evaluation cannot be directly translated to a paediatric population.

Titration of sevoflurane anesthesia to optimize the time to regain airway reflexes in patients undergoing elective surgery: A randomized clinical trial comparing desflurane and sevoflurane anesthesia.

BACKGROUND: Desflurane has adverse environmental effects, but has clinical advantages to speed emergence and return of protective airway reflexes compared with sevoflurane. We hypothesized that weaning of the inspired sevoflurane during the final 15 minutes of surgery would eliminate differences in airway reflex recovery between these agents. METHODS: After obtaining IRB approval and informed consent, 40 patients undergoing elective surgery (≥1-hour) randomly received desflurane or sevoflurane. Patients swallowed 20 mL of water without drooling or coughing, and then received sedation and PONV pre-medication. Anesthesia was induced using propofol and fentanyl and maintained with desflurane or sevoflurane through a laryngeal mask airway maintaining a bispectral index of 45-50 and 50-60 during the final 15 minutes before surgery end. Cardiorespiratory variables and age-adjusted minimal alveolar concentration were recorded. The duration between anesthetic discontinuation and first appropriate response to command was measured; the laryngeal mask airway was removed. Two minutes after responding to command, patients were positioned semi-upright and attempted to swallow water. If successful swallowing was not achieved, the test was repeated every 4 minutes after each failure until successful swallowing was achieved. RESULTS: Average anesthetic concentration and bispectral index was similar in patients receiving desflurane vs sevoflurane. Response times after discontinuation of anesthetics were similar. There were no differences in the recovery of swallowing ability between desflurane and sevoflurane groups. CONCLUSION: Weaning of sevoflurane during the final 15 minutes of surgery eliminates clinical advantages of the more rapid return of airway reflexes with desflurane.

Effects of GABA-B agonist baclofen on esophageal motility: Studies using high-resolution manometry.

BACKGROUND/AIM: Baclofen inhibits transient lower esophageal sphincter (LES) relaxation. This study aimed to investigate the effect of baclofen on esophageal peristaltic function and contraction reserve in healthy adults using high-resolution manometry (HRM). METHODS: Fifteen subjects underwent HRM with ten water swallows and five multiple rapid swallows (MRS) 90 minutes after oral intake of either baclofen or placebo on separate days at least 1 week apart. HRM parameters assessed included esophagogastric junction contractile integral (EGJ-CI), resting LES pressure, 4-second integrated relaxation pressure (IRP-4s), distal contractile integral (DCI), distal latency, peristaltic breaks, resting upper esophageal sphincter (UES) pressure, and contractile response to MRS. RESULTS: Baclofen significantly increased EGJ-CI (P = .007), IRP-4s (P = .003), and LES pressure (P = .004). UES pressure, latency, and DCI were similar between baclofen and placebo (P = .87, P = .84, and P = .54, respectively). There was no difference in contractile response and peristaltic augmentation following MRS between baclofen and placebo (93% vs 100%, P = .30; 53% vs. 73%, P = .26, respectively). CONCLUSIONS: Baclofen increases resting LES pressure and EGJ barrier function, but has no effect on primary peristalsis or contraction reserve.