Thesis (Ph. D.)--University of Chicago, 1906. / Also issued in print.

Thesis (Ph. D.)--University of Chicago, 1906. / eContent provider-neutral record in process. Description based on print version record.

Rationale: Chronic cough (cough >8 weeks) is common, leads to an impaired quality of life, and is difficult to treat. Despite intensive investigation, ~40% of patients referred to a specialist cough clinic will remain resistant to treatment targeted at peripheral triggers such as reflux disease, rhino-sinusitis or airways inflammation. An improved understanding of underlying mechanisms in such patients would facilitate drug development. I propose that there are several important similarities between pain and cough that can be exploited better to understand underlying mechanisms. In chronic pain, a long-lasting up-regulation of afferent pain processing may be generated by changes within the central nervous system, mediated by the NMDA receptor and/or by impaired inhibitory mechanisms. A similar central neuronal up-regulation of cough may also be responsible for the pathogenesis of chronic cough (CC). Methods: A series of experimental studies were performed to address this hypothesis. Firstly, the anti-tussive and analgesic effect of ketamine, an NMDA receptor antagonist, was investigated in CC patients and healthy controls (HC). Pain thresholds were measured using electrical stimulation in the oesophagus, pharynx and chest wall. Cough sensitivity was measured using standard capsaicin cough challenges. Secondly, I designed and tested novel capsaicin cough challenges in CC patients, asthmatics (A) and HC. ED50 (dose inducing and least 50% maximal cough frequency) and Cmax (maximal cough frequency) was compared by group and gender. Finally, I investigated 2 independent mechanisms of cough inhibition. Results:(i) CC patients, but not HC, had cough induced by oesophageal electrical stimulation, whilst pain thresholds were similar. Ketamine had a significant analgesic effect but no antitussive effect in CC or HC.(ii) CC patients had both cough hypersensitivity (lower ED50) and cough hyper-responsiveness (higher Cmax) on full capsaicin dose-response curves. (iii) Both a painful cold stimulus applied to the hand and conscious cough suppression significantly inhibited capsaicin-induced cough responses in CC and HC.Conclusions:CC patients exhibited increased oesophageal sensitivity to cough, but not pain, providing evidence for a process of central sensitisation in the brainstem. Higher capsaicin-induced cough frequencies in CC may also be mediated by an increased gain within the CNS, possibly because of failed tonic inhibitory mechanisms. Furthermore, CC patients may have poorer conscious control of coughing. In conclusion, an improved understanding of mechanisms in cough will provide a strong scientific rationale for the development of novel therapeutics.

Background: Cough Reflex Testing (CRT) has been shown to be useful in the challenging task of identifying silent aspiration (aspiration without a cough response). With the emergence of the routine clinical use of CRT in the acute stroke population, the following clinical conundrum often arises: Does passing a previously failed CRT mean the risk of silent aspiration has resolved? The purpose of this study was to evaluate the association between change in laryngeal cough threshold sensitivity and change in PAS (Penetration Aspiration Scale) score within the acute stage post-stroke. Methods: This was a prospective longitudinal pilot study of 20 acute stroke patients utilizing a Cough Reflex Threshold Test (CRTT) at 0.4M, 0.6M and 0.8M citric acid concentrations and Fiberoptic Endoscopic Evaluation of Swallowing (FEES). A cough response threshold was obtained from the CRTT and a PAS (penetration aspiration scale) score from FEES. Inclusion criteria required a PAS score of 4 or above on preliminary FEES or impaired CRT threshold as defined by weak or failed cough test result at 0.8M citric acid concentration. Both test methods were repeated every four days for 20 days or until the participant no longer aspirated/penetrated and had a normal result on CRTT on two consecutive assessment sessions. Agreement between changes in the two tests was evaluated using the Cohen’s Kappa statistic. Results: Eighteen of the twenty participants in this study aspirated on initial assessment, ten of which were silent. One participant continued to aspirate at study completion. On initial assessment eleven participants had a C2 response threshold at 0.4M citric acid concentration and three participants failed to reach threshold at 0.8M citric acid concentration. At study completion, 18 participants had a C2 response threshold at 0.4M citric acid concentration and one participant failed to reach threshold at 0.8M citric acid concentration. During the study, sixty-six re-assessments took place; there were fifteen incidences of improved cough response threshold on re-assessment and thirty-one incidences of improved PAS score. There was no significant agreement between improved laryngeal cough reflex threshold and improved PAS score during the acute stage Kappa = 0.0598 (p <.0.574), 95% CI (- 0.1496- 0.2692). Conclusion: Significant limitations of this study included small data set and potential flooring effect of the CRT. Due to the limitations of this study, no conclusions can be made as to the appropriateness of reinstating oral intake based on passing a previously failed CRT.

One of the most elusive challenges in the diagnosis and treatment of dysphagia is the reliable identification of silent aspiration (aspiration in the absence of cough). The citric acid inhalation cough challenge offers potential for aiding in identification of silent aspiration; however clinical application of this technique is currently problematic due to an absence of normative data. Therefore, this study aimed to establish a normative data set for the Citric- Acid Inhalation Cough Challenge, as administered with facemask method. 80 healthy subjects will participate in this study, constituting 2 age groups: above and below 60 years, with equal gender representation. On 3 separate trials, they will be asked to passively inhale, via a facemask, nebulised citric acid of concentrations ranging from 08M to 2.6M with placebo interspersed. ‘Natural cough thresholds’ (NCT) and ‘Suppressed Cough Thresholds’ (SCT) will be reached when subjects cough on at least 2 out of 3 trials. The majority (92.5%) of participants reached Natural Cough Threshold by 0.8M, with 68% demonstrating Suppressed Cough Threshold also at this concentration. There were no significant differences found between males and females (p<0.05) for either NCT (p=0.9885) or SCT (p=0.44). Whilst no difference was found between youngers and elders for NCT (p=0.7254), there was a significant difference for SCT (p=0.018), with youngers better able to suppress cough. Over 90% of healthy people were found to elicit cough at 0.8M, inferring that this level would be an adequate guide for use by clinicians testing for presence/absence of cough.

Cough is one of the most common symptoms prompting patients to be seen by health care providers in the United States. Persistent cough can disrupt daily activities such as conversation, eating, breathing, and sleeping, and it can become extremely debilitating both physically and mentally. Pharmacological treatments include dextramethorphan, opioid cough suppressants, benzonatate, inhaled ipratropium, and guaifenesin. Successful cough suppression has also been demonstrated in several studies with the use of nebulized lidocaine. Nebulized lidocaine also appears to be well tolerated by patients with minimal side effects including dysphonia, oropharyngeal numbness, and bitter taste. Studies conducted thus far have been small, so larger randomized control trials comparing nebulized lidocaine to placebo need to be conducted in the future.

Cough is one of the most common symptoms prompting patients to be seen by health care providers in the United States. Persistent cough can disrupt daily activities such as conversation, eating, breathing, and sleeping, and it can become extremely debilitating both physically and mentally. Pharmacological treatments include dextramethorphan, opioid cough suppressants, benzonatate, inhaled ipratropium, and guaifenesin. Successful cough suppression has also been demonstrated in several studies with the use of nebulized lidocaine. Nebulized lidocaine also appears to be well tolerated by patients with minimal side effects including dysphonia, oropharyngeal numbness, and bitter taste. Studies conducted thus far have been small, so larger randomized control trials comparing nebulized lidocaine to placebo need to be conducted in the future.

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