Diabetes insipidus after discontinuation of vasopressin infusion for septic shock.

WHAT IS KNOWN AND OBJECTIVE: Despite widespread use of vasopressin for the treatment of septic shock, few cases of diabetes insipidus (DI) following its discontinuation have been reported. CASE SUMMARY: A 54-year-old man presented with pneumonia progressing to septic shock, requiring norepinephrine and vasopressin for refractory hypotension. After clinical improvement, the patient on 3 separate occasions developed polyuria and severe hypernatremia upon discontinuation of vasopressin, with prompt recovery upon its resumption. WHAT IS NEW AND CONCLUSION: Occurrence of DI upon discontinuation of vasopressin infusion appears to be rare, but incidence may be underestimated due to a paucity of published reports. Actual incidence and underlying mechanism of this phenomenon remain to be elucidated.

Consumer attitudes on cough and cold: US (ACHOO) survey results.

OBJECTIVE: The Attitudes of Consumers Toward Health, Cough, and Cold (ACHOO) survey was developed to better inform health care providers on the natural history and impact of common cold and cough, and related consumer experience and behaviors. RESEARCH DESIGN AND METHODS: Randomly selected US Internet/mobile device users were invited to participate in an online survey (N = 3333) in October 2012. Response quotas modeled upon 2010 US Census data ensured a demographically representative sample. To reduce potential bias from the quota design, 75% of the completed surveys were randomly selected as the primary analysis pool. MAIN OUTCOME MEASURES: Survey questions assessed participant demographics, frequency and duration of cough/cold symptoms, impact of symptoms on daily life, treatment preferences, and knowledge about cough/cold pathophysiology. RESULTS: In the past year, 84.6% of respondents had experienced at least one cold. Colds typically started with sore/scratchy throat (39.2%), nasal congestion (9.8%), and runny nose (9.3%) and lasted 3-7 days. Cough, the most common cold symptom (73.1%), had a delayed onset (typically 1-5 days after cold onset) and a long duration (>6 days in 35.2%). Nasal congestion and cough were the most bothersome symptoms. Many respondents waited until symptoms were 'bad enough' (42.6%) or multiple symptoms were present (20.2%) before using nonprescription medications. Drivers of choice included effectiveness in relieving symptoms, safety, and past experience. Respondents rarely consulted clinicians regarding treatment, and more than three-quarters had never received instructions from a clinician on how to choose a nonprescription cough/cold medication. Misperceptions regarding etiology and treatment of the common cold were prevalent. The main limitation is potential recall bias, since respondents had to recall cough/cold episodes over the prior year. CONCLUSIONS: The ACHOO survey confirms that cold is a common, bothersome experience and that there are gaps in consumers' knowledge of pathophysiology and appropriate management of cough/cold.

Antitussive drugs--past, present, and future.

Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.

Chronic cough associated with interferon/ribavirin therapy for hepatitis C.

WHAT IS KNOWN AND OBJECTIVE: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy. CASE SUMMARY: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2-6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C(5) , the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0·016). WHAT IS NEW AND CONCLUSION: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough.

Alternative mechanisms for tiotropium.

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Clinical cough III: measuring the cough response in the laboratory.

As interest in clinical cough research grows, measurement of cough reflex sensitivity will assume an increasingly important role. With proper equipment and meticulous attention to methodological details, cough reflex sensitivity can be safely, accurately, and reproducibly determined. Such precise measurement allows the evaluation of the effect of pharmacological or nonpharmacological interventions on the sensitivity of the cough reflex, or the comparison of cough reflex sensitivity between different subject populations. In addition to the method, other vital components of optimal cough challenge testing include proper interpretation of data and appropriate selection of study populations.

Effect of smoking cessation on cough reflex sensitivity.

Recent studies have shown that cigarette smokers have diminished cough reflex sensitivity compared with nonsmokers. The current authors proposed a mechanism of chronic cigarette smoke-induced desensitisation of airway cough receptors. To investigate this hypothesis, cough sensitivity to inhaled capsaicin (C5) in chronic smokers was measured both while they were actively smoking and 2, 6, 12 and 24 weeks after smoking cessation. In total, 29 subjects underwent baseline capsaicin challenge while smoking and 2 weeks after smoking cessation. Mean+/-sem log C5 fell from 1.86+/-0.12 to 1.60+/-0.12, demonstrating significant enhancement of cough reflex sensitivity. Of the total, 20, 18 and 14 subjects successfully abstained from smoking for 6, 12 and 24 weeks, respectively. Mean log C5 values after 12 and 24 weeks of smoking cessation were significantly diminished from baseline. In a control group of smokers, mean log C5 did not decrease from baseline after 6, 12 and 24 weeks. Overall, the log C5 profile of the smoking cessation group showed a clear, linearly decreasing trend over time compared with the control group. Even after many years of smoking, cough sensitivity is enhanced as early as 2 weeks after smoking cessation. Given the importance of an intact cough reflex, these changes may provide clinical benefit.

Cough. 4: Cough in asthma and eosinophilic bronchitis.

Airway eosinophilia and cough may be associated with asthma and with non-asthmatic eosinophilic bronchitis. Whether cough variant asthma and eosinophilic bronchitis are distinct entities or a pathophysiological spectrum needs further examination.

Ethnic and gender differences in cough reflex sensitivity.

BACKGROUND: Although recent studies have suggested that the cough reflex is more sensitive in women than in men, ethnic differences in cough reflex sensitivity have not previously been investigated. OBJECTIVES: To evaluate ethnic and gender differences in cough reflex sensitivity. METHODS: We performed capsaicin cough challenge testing in 182 healthy volunteers of three distinct ethnic groups: Caucasian (white, non-Hispanic, of European origin), Indian (originating from the Indian subcontinent) and Chinese. The concentration of capsaicin inducing 2 or more (C2) and 5 or more coughs (C5) was determined in each subject. RESULTS: Mean (+/-SEM) values for log C5 demonstrated that, within each ethnic group, the cough reflex was more sensitive in women: p = 0.00002 for Caucasian subjects; p = 0.003 for Indian volunteers; and p = 0.002 for Chinese subjects. Examination of C2 data yielded similar results. When subjects were evaluated by gender, multivariate analysis of variance demonstrated no ethnic differences in sensitivity to capsaicin. CONCLUSION: Our data do not support the presence of significant ethnic differences in cough reflex sensitivity, but do confirm previous data demonstrating lower cough thresholds in women.

Effect of the cyclooxygenase-2 inhibitor celecoxib on bronchial responsiveness and cough reflex sensitivity in asthmatics.

Cyclooxygenase (COX), an essential enzyme in the pathway of prostaglandin formation from arachidonic acid, exists in two isoforms. Cyclooxygenase-1 (COX-1) is expressed under normal physiologic conditions, whereas COX-2, the inducible isoform, is associated with inflammation. Recent studies have linked COX-2 induction to the asthmatic inflammatory response, but potentially beneficial results, such as enhanced production of antiinflammatory and bronchoprotective substances, may also occur. The aim of the present study was to investigate the effect of selective COX-2 inhibition on bronchial responsiveness and cough reflex sensitivity. Eight adult subjects with stable asthma underwent spirometry, bronchoprovocation challenge with methacholine, and cough challenge testing with capsaicin, before and after a 7 day course of the COX-2 inhibitor celecoxib (200 mg orally, twice daily) and placebo, in a randomized, double-blind, crossover fashion. No significant changes in pulmonary function, bronchial responsiveness, or cough reflex sensitivity were induced by celecoxib. It appears, therefore, that 1 week of therapy with celecoxib does not significantly affect basal airway tone, nor the afferent airway receptors controlling bronchoconstriction and cough. However, the results of this trial cannot be extrapolated to subjects with severe asthma, or those suffering an asthmatic exacerbation. In such conditions of enhanced inflammatory response, the role of selective COX-2 inhibition remains to be elucidated.

Baclofen-induced cough suppression in cervical spinal cord injury.

OBJECTIVE: To determine the effect of the GABA-agonist baclofen on cough reflex sensitivity in subjects with cervical spinal cord injury (C-SCI). Baclofen has been shown to inhibit the cough reflex in able-bodied volunteers. DESIGN: Prospective, nonrandomized control trial. SETTING: Veterans Affairs medical center with large outpatient SCI population. PARTICIPANTS: Twelve adult males (11 outpatients) with C-SCI chronically maintained on oral baclofen for the treatment of muscle spasm. INTERVENTION: Subjects underwent cough challenge testing with inhaled capsaicin. The concentrations (microM) of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs were determined. Mean values for log C2 and log C5 were compared with a control group of outpatients with C-SCI not receiving baclofen. RESULTS: Subjects treated with baclofen had a significantly higher cough threshold (diminished cough reflex sensitivity) than control subjects. Mean (+/- standard error of the mean) values for log C2 in study subjects and controls were 1.28 +/- .16 and .65 +/- .15, respectively (p = .009). Mean values for log C5 in subjects receiving baclofen and in control subjects were 2.20 +/- .22 and 1.43 +/- .23, respectively (p = .024). Subjects and controls did not differ in terms of age, spirometric parameters, or duration of injury. CONCLUSIONS: The results suggest that chronic therapy with baclofen diminishes cough reflex sensitivity in subjects with C-SCI. The clinical significance of this finding remains to be elucidated.

Effect of the GABA-agonist baclofen on bronchial responsiveness in asthmatics.

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter. Recently, the presence of GABA and its receptors has been confirmed in peripheral tissues, including the lungs. GABA and the GABA agonist baclofen have been shown in animal studies to inhibit airway responsiveness to various bronchoconstricting agents. The results of these investigations suggest the possibility of a role for baclofen in the therapy of human airway hyperreactivity. To investigate this question, a randomized, double-blind, placebo-controlled, cross-over study was performed to evaluate the effect of a 14-day course of oral baclofen (10 mg three times daily) on pulmonary function and bronchial responsiveness to methacholine in a group of six stable asthmatics. In five of six subjects, hyperresponsiveness was enhanced after therapy with baclofen. Mean (+/- SEM) log PC(20)pre-and post-baclofen were 0.160 +/- 0.247 and -0.223 +/- 0.282, respectively (P=0.023). Baseline pulmonary function (FEV(1)) was unaffected by baclofen. The mechanism(s) underlying this apparent paradoxical enhancement by baclofen of bronchial responsiveness remains speculative, but may be relevant to the recently-proposed concept of dysfunction in asthmatics of prejunctional GABA receptors, whose normal role may be to inhibit cholinergic contraction of bronchial smooth muscle.

Effect of zafirlukast on cough reflex sensitivity in asthmatics.

In patients with asthma, increased sensitivity of airway sensory nerves may be involved in producing bronchospasm and cough. To evaluate the effect of a leukotriene-modifying agent on cough reflex sensitivity, we measured the cough response to inhaled capsaicin before and after a 1 4-day course of therapy with zafirlukast, a cysteinyl leukotriene receptor antagonist, in a group of stable asthmatics. The concentration of capsaicin inducing two or more (C2) and five or more (C5) coughs was not altered by zafirlukast, even in those subjects demonstrating a significant change (increment or decrement) in forced expiratory volume in 1 sec (FEV1). These findings support previous evidence that cough and bronchoconstriction are modulated by distinct neural pathways.

"Crack" cocaine-induced syndrome mimicking sarcoidosis.

A 39-year-old man with a history of frequent "crack" cocaine use of several years' duration presented with progressive dyspnea. Evaluation revealed bilateral interstitial pulmonary infiltrates and hilar adenopathy, diffuse pulmonary uptake of gallium, and markedly elevated serum angiotensin-converting enzyme activity. Open lung biopsy revealed interstitial and perivascular collections of histiocytes containing refractile, polarizable material, presumably inhaled along with the cocaine. Paratracheal lymph nodes were enlarged, reactive, and contained similar polarizable material. The well-formed, non-necrotizing granulomata characteristic of sarcoidosis were not present in either tissue specimen. To our knowledge, the association of chronic crack cocaine inhalation with this constellation of clinical findings, typically seen in sarcoidosis, has not previously been described.

Cough reflex sensitivity in subjects with cervical spinal cord injury.

An effective cough requires an intact cough reflex as well as adequate respiratory muscle function to generate elevated intrathoracic pressures. Since the major muscles of expiration are innervated by the first thoracic segment and below, transection of the cervical spinal cord results in severely compromised expiratory function and cough. To investigate the effects of cervical spinal cord injury (C-SCI) on cough reflex sensitivity, we measured responsiveness to inhaled capsaicin in 12 male subjects with chronic C-SCI and compared findings to those from a control group of 50 able-bodied men. The concentrations (microM) of capsaicin inducing two or more (C2) and five or more coughs (C5) did not significantly differ between the two groups. Mean (+/- SEM) values for log C2 in subjects with C-SCI and control subjects were 0.65 +/- 0.15 and 0.87 +/- 0.07, respectively (p = 0.15). Mean values for log C5 in subjects with C-SCI and control subjects were 1.43 +/- 0.23 and 1.41 +/- 0.08, respectively (p = 0.94). We conclude that cough reflex sensitivity is preserved after C-SCI, and that ineffective cough in this population results primarily from the loss of innervation of respiratory muscles.