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.

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.

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 effect of the GABA-agonist baclofen.

BACKGROUND: gamma-Aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in peripheral tissues, including the lung. The GABA-agonist baclofen has been shown, in animal studies, to inhibit cough via a central mechanism, but has not been investigated in humans (to our knowledge). STUDY OBJECTIVE: To evaluate the antitussive effect of baclofen in normal human subjects. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Academic medical center. PARTICIPANTS: Twenty healthy, adult volunteers. INTERVENTIONS: Subjects underwent cough challenge with inhaled capsaicin before and after a 14-day course of baclofen, 10 mg three times daily, or placebo. Capsaicin cough threshold (C5) was defined as the concentration of inhaled capsaicin inducing five or more coughs. RESULTS: Subjects receiving baclofen (n=10) demonstrated a significant elevation of capsaicin cough threshold compared with placebo subjects (n=10). Mean delta log C5 after treatment was 0.48+/-0.19 (SEM) for the baclofen group, and -0.06+/-0.12 for the placebo group (p=0.024). Six of 10 subjects receiving baclofen, but none of the 10 subjects receiving placebo, demonstrated a fourfold or greater increase in capsaicin cough threshold (p=0.0054). CONCLUSION: The antitussive activity of low-dose, oral baclofen demonstrated in this study supports further investigation of this drug, or other GABA-agonists, for a potential therapeutic role in the treatment of pathologic cough.

The influence of gender on cough reflex sensitivity.

BACKGROUND: The more common occurrence in women of cough due to angiotensin-converting enzyme inhibitors raises the possibility of gender-related differences in the sensitivity of the cough reflex. Of two recent studies that evaluated cough response to inhaled capsaicin in normal subjects, one demonstrated heightened sensitivity of the cough reflex in women compared with men, while the other revealed no gender-related differences. To further investigate this question, we reviewed our experience with cough challenge testing in normal volunteers. STUDY OBJECTIVE: To compare cough reflex sensitivity in healthy adult female and male subjects. DESIGN: Retrospective data analysis. SETTING: Academic medical center. PARTICIPANTS: One hundred healthy volunteers (50 male, 50 female). INTERVENTIONS: Subjects inhaled capsaicin in ascending, doubling concentrations until the concentration inducing five or more coughs (C5) was reached. In addition, the concentration inducing two or more coughs (C2; cough threshold) was measured. RESULTS: Mean log C5 was significantly lower in women than in men: 1.02+/-0.09 (SEM) microM vs 1.41+/-0.08 microM, respectively (p=0.002). Log C2 (cough threshold) was also significantly lower in female subjects: 0.534+/-0.068 microM vs 0.870+/-0.065 microM in male subjects (p=0.00058). CONCLUSION: Healthy women have a more sensitive cough reflex than do healthy men. The reasons for this significant gender difference remain to be elucidated, but may involve a heightened sensitivity, in women, of the sensory receptors within the respiratory tract that mediate cough.

Inhibition of bronchial hyperresponsiveness by the GABA-agonist baclofen.

gamma-Aminobutyric acid (GABA) is a well-known inhibitory transmitter of the central nervous system. Recently, the presence of GABA and its receptors has been confirmed in peripheral tissues, including lung tissue. gamma-Aminobutyric acid 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. We recently showed that subjects with cervical spinal cord injury (quadriplegia) uniformly exhibit hyperresponsiveness to methacholine. The interruption of sympathetic airway innervation and resultant unopposed cholinergic tone occurring after transection of the cervical spine are thought to explain this phenomenon. We compared bronchial responsiveness with methacholine (PC20) in a control group of otherwise healthy quadriplegic nonsmokers (n = 8) with a similar group of subjects (n = 6) maintained on baclofen for the relief of muscle spasm. Mean PC20 (mg/ml) among the control group was 1.42 +/- 1.6(SD) vs 15.0 +/- 9.1 in the baclofen group (p = 0.001). The inhibition of bronchial hyperresponsiveness in subjects with cervical spinal cord injury maintained on chronic baclofen therapy suggests the drug's ability to block neuronal acetylcholine release within airways, as well as a possible direct effect on airway smooth muscle. This action of baclofen, along with its documented ability in animal lung to inhibit release of other inflammatory mediators, supports further investigation of this drug as a potential therapeutic agent for asthma treatment.

Bronchial hyperresponsiveness after cervical spinal cord injury.

Cervical spinal cord injury results in interruption of sympathetic airway innervation, which originates from the upper thoracic spine, whereas parasympathetic nerve supply, arising in the vagal nuclei of the brainstem, remains intact. To assess the effect of such an altered neural environment on airway reactivity, bronchoprovocation testing was performed on eight subjects with nonacute traumatic lesions of the cervical spine, all of whom were lifetime nonsmokers without history of respiratory symptoms prior to their injury. Bronchial challenge was subsequently repeated after pretreatment with the anticholinergic agent, ipratropium bromide, an inhibitor of airway muscarinic receptors. All subjects demonstrated hyperresponsiveness to methacholine (the concentration of methacholine producing a fall in FEV1 of 20 percent from baseline [PC20] = 1.42 +/- 1.61 [SD] mg/ml). Airway hyperreactivity was completely blocked by pretreatment with inhaled ipratropium bromide (mean PC20 > 25 mg/ml [p < 0.0001]). The bronchial hyperresponsiveness observed in this population most likely reflects the loss of sympathetic airway innervation and resultant unopposed cholinergic bronchoconstrictor tone which results from transection of the cervical spine. Blockade of methacholine hyperresponsiveness with ipratropium bromide suggests a muscarinic receptor-mediated phenomenon.

Primary endobronchial actinomycosis in association with foreign body aspiration.

A 66-year-old diabetic man presented with a bilobar pneumonia two months after aspiration of a chicken bone. Flexible fiberoptic bronchoscopy demonstrated a mass in the bronchus intermedius. Histologic examination of endobronchial biopsy specimens revealed bone fragments, vegetable matter, and sulfur granules containing Actinomyces organisms. The patient responded to bronchoscopic removal of the foreign body and penicillin therapy. To our knowledge, the association of actinomycotic infection with an aspirated endobronchial foreign body has not previously been reported.

Postobstructive pulmonary edema induced by endotracheal tube occlusion.

Pulmonary edema is a well-described complication of upper airway obstruction, most commonly caused in adults by postanesthetic laryngospasm. The mechanism initiating the formation of postobstructive pulmonary edema is believed to be the markedly negative intrapleural pressure generated by a forceful inspiratory effort against an obstructed extrathoracic airway. We herein describe a young, male patient who developed pulmonary edema postoperatively, upon emergence from anesthesia, after performing repeated, forceful inspiratory maneuvers directed against an endotracheal tube on which he had bitten down, thereby occluding it. To our knowledge, such an etiology of postobstructive pulmonary edema has not previously been described.

Effect of angiotensin-converting enzyme inhibition on bronchial responsiveness.

The effect of angiotensin-converting enzyme (ACE) inhibition on bronchial responsiveness has not been clearly established. Because ACE degrades bradykinin and substance P, inhibition of the enzyme may lead to accumulation of these potent bronchoconstrictors in the lung, potentially leading to enhanced bronchial reactivity or bronchospasm. Previous studies of the effect of ACE inhibition on airway responsiveness have yielded conflicting results. A randomized, double-blind, placebo-controlled study was therefore conducted to evaluate the effect of a 14-day course of oral lisinopril (10 mg for days 1-3, 20 mg for days 4-14) on bronchial responsiveness to inhaled methacholine in a group of healthy volunteers. No significant change in methacholine responsiveness occurred in any of the participants receiving lisinopril. The mean ( +/- SD) concentration of methacholine producing a decrease in FEV1 of 20% from baseline (PC20; mg/mL) was 23.3 +/- 5.0 before the study and 23.5 +/- 4.5 at the end of the study for the lisinopril group, and 23.0 +/- 4.6 before the study and 21.8 +/- 6.9 after the study for the placebo group. The 14-day course of ACE inhibitor therapy did not enhance nonspecific bronchial responsiveness in healthy volunteers.

Inhibition of capsaicin-induced cough by the gamma-aminobutyric acid agonist baclofen.

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA-agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14-day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low-dose, oral baclofen given once daily. Forty-one healthy volunteers were randomly assigned in a double-blind manner to receive a 28-day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once-daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA-agonists as potential therapeutic agents for chronic, nonproductive cough.

"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.

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.

Use of baclofen to suppress cough induced by angiotensin-converting enzyme inhibitors.

OBJECTIVE: To determine whether baclofen can suppress the cough induced by angiotensin-converting enzyme (ACE) inhibitors. DESIGN: Prospective, open-label, clinical trial of a 4-week course of low-dose oral baclofen (5 mg tid days 1-7, 10 mg tid days 8-28). SUBJECTS: Seven patients with severe, persistent ACE inhibitor-induced cough. SETTING: University-affiliated teaching hospital. MAIN OUTCOME MEASURES: Study participants kept daily diaries monitoring the frequency of cough during and after completion of baclofen therapy. RESULTS: All subjects demonstrated diminution of cough after initiation of baclofen. Initial improvement was noted by a mean of 4.0 days (range 3-6), and maximal improvement during treatment was achieved by a mean of 10.7 days (range 5-15). In addition, all subjects demonstrated persistent suppression of cough (range 25-74 d) after discontinuation of the study drug. CONCLUSIONS: Low-dose oral baclofen therapy caused a prolonged antitussive effect in all subjects without inducing any adverse reactions. Baclofen may offer an alternative to the discontinuation of ACE inhibitor therapy in patients for whom these drugs are required.

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.