The impact of change of renal replacement therapy modality on sleep quality in patients with end-stage renal disease: a systematic review and meta-analysis.

BACKGROUND: Sleep disorders are common and multi-factorial in patients with advanced chronic kidney disease and end-stage renal disease (ESRD). Sleep disorders and disturbance have a negative impact on wellbeing and quality of life. OBJECTIVE: To assess the impact of a change in renal replacement therapy (RRT) modality on sleep quality and sleep disturbance in patients with ESRD. DATA SOURCES: Multiple electronic databases were searched without publication type/period restrictions. The reference lists of all included articles were manually searched for additional citations. Non-published data was identified by hand searching key conference abstracts. STUDY ELIGIBILITY CRITERIA: Participants of interest were adult patients with ESRD requiring RRT [conventional haemodialysis (HD), short daily HD, nocturnal HD, continuous ambulatory peritoneal dialysis (CAPD), continuous cycler-assisted peritoneal dialysis (CCPD) or transplantation]. The exposure or intervention of interest was switch of RRT modality. STUDY APPRAISAL: Two reviewers independently assessed all studies for inclusion and extracted relevant data. RESULTS: Sixteen studies with a combined total of 670 patients and 191 controls were included for review and described in detail. Looking specifically at restless leg syndrome, symptoms resolved in over 60% of affected patients with a switch to increased intensity RRT (either intensive HD, CCPD or transplant). Meta-analysis of the nine studies that looked specifically at sleep apnoea parameters again favoured intensive RRT over standard/conventional RRT (conventional HD or CAPD) with statistical significance [Risk ratio 0.66 (95% CI 0.51-0.84)]. Meta-analysis of all studies favoured a switch to increased intensity RRT in terms of overall sleep quality, with statistical significance [Risk ratio 0.58 (95% CI 0.40-8.83)]. LIMITATIONS: Restriction to the English language may have introduced selection bias. Funnel plot analysis suggested there was also an element of publication bias. Studies were heterogeneous in terms of patient selection, means of sleep quality assessment and modality switch. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Sleep disturbance, sleep apnoea and restless legs syndrome all tend to improve when a switch is made to intensive dialysis or transplant. This is important information for patients struggling with disturbed sleep and marked fatigue. This hypothesis-generating review highlights the need for more high quality prospective research in the area.

Hospital Resource Utilisation by Patients with Community-Acquired Pneumonia.

Little data is available on the resource utilisation of patients admitted with Community-Acquired Pneumonia (CAP) in Ireland. A retrospective review of 50 randomly-selected patients admitted to Beaumont Hospital with CAP was undertaken. The mean length of stay of patients with CAP was 12 days (+/- 16 days). All patients were emergency admissions, all had a chest x-ray, a C-reactive protein blood test, and occupied a public bed at some point during admission. Common antimicrobial therapies were intravenous (IV) amoxicillin/clavulanic acid and oral clarithromycin; 60% received physiotherapy. The estimated mean cost of CAP per patient was €14,802.17. Costs arising from admission to hospital with CAP are substantial, but efforts can be undertaken to ensure that resources are used efficiently to improve patient care such as discharge planning and fewer in-hospital ward transfers.

Eosinophil peroxidase induces the expression and function of acid-sensing ion channel-3 in allergic rhinitis: in vitro evidence in cultured epithelial cells.

BACKGROUND: Acid-sensing ion channels (ASIC) are a family of acid-activated ligand-gated cation channels. As tissue acidosis is a feature of inflammatory conditions, such as allergic rhinitis (AR), we investigated the expression and function of these channels in AR. OBJECTIVES: The aim of the study was to assess expression and function of ASIC channels in the nasal mucosa of control and AR subjects. METHODS: Immunohistochemical localization of ASIC receptors and functional responses to lactic acid application were investigated. In vitro studies on cultured epithelial cells were performed to assess underlying mechanisms of ASIC function. RESULTS: Lactic acid at pH 7.03 induced a significant rise in nasal fluid secretion that was inhibited by pre-treatment with the ASIC inhibitor amiloride in AR subjects (n = 19). Quantitative PCR on cDNA isolated from nasal biopsies from control and AR subjects demonstrated that ASIC-1 was equally expressed in both populations, but ASIC-3 was significantly more highly expressed in AR (P < 0.02). Immunohistochemistry confirmed significantly higher ASIC-3 protein expression on nasal epithelial cells in AR patients than controls (P < 0.01). Immunoreactivity for EPO+ eosinophils in both nasal epithelium and submucosa was more prominent in AR compared with controls. A mechanism of induction of ASIC-3 expression relevant to AR was suggested by the finding that eosinophil peroxidase (EPO), acting via ERK1/2, induced the expression of ASIC-3 in epithelial cells. Furthermore, using a quantitative functional measure of epithelial cell secretory function in vitro, EPO increased the air-surface liquid depth via an ASIC-dependent chloride secretory pathway. CONCLUSIONS: This data suggests a possible mechanism for the observed association of eosinophils and rhinorrhoea in AR and is manifested through enhanced ASIC-3 expression.

Therapy with omalizumab for patients with severe allergic asthma improves asthma control and reduces overall healthcare costs.

BACKGROUND: Patients with asthma who have persistent symptoms despite treatment with inhaled steroids and long-acting beta agonists are considered to have severe asthma. Omalizumab is a monoclonal antibody directed against IgE, which is used as an add-on treatment for patients who have severe persistent allergic asthma. AIMS: The aim of this study was to assess the clinical benefit and healthcare utilisation of patients who responded to omalizumab therapy and to establish an overall cost implication. METHODS: This was an observational retrospective cohort study designed to investigate the effect of omalizumab on exacerbations of asthma before and after 6 months of treatment in Irish patients. RESULTS: Centres who had treated patients with severe allergic asthma for the 6 months prior and post omalizumab treatment were audited with a standardised assessment tool. Sixty-three (32 male) patients were studied. In the 6 months prior to omalizumab 41 of 63 (66%) had been hospitalised, and this fell to 15 of 63 (24%), p < 0.0001 in the 6 months after treatment was started. Hospital admissions reduced from 2.4 ± 0.41 to 0.8 ± 0.37 and the mean number of bed days occupied was reduced from 16.6 ± 2.94 to 5.3 ± 2.57 days, p < 0.001. The number of oral corticosteroid doses used fell from 3.1 ± 0.27 to 1.2 ± 0.17, p < 0.001. The overall cost saving per omalizumab responder patients for 6 months was 834. CONCLUSIONS: Six months therapy with omalizumab reduced the number of bed days, the number of hospitalisations and the use of oral corticosteroids compared to the 6 months prior to commencement. Despite the cost of the additional therapy there were overall savings in health costs.

Somnolence in adult craniopharyngioma patients is a common, heterogeneous condition that is potentially treatable.

CONTEXT AND OBJECTIVE: Somnolence and obesity are prevalent in craniopharyngioma patients. We hypothesized that somnolence was because of obstructive sleep apnoea in craniopharyngioma patients. DESIGN, PATIENTS AND MEASUREMENTS: We assessed prevalence of somnolence and sleep apnoea in 28 craniopharyngioma and 23 obese controls attending a tertiary referral centre, by means of the Epworth Sleepiness Score (ESS) and polysomnography. All subjects with sleep apnoea were offered continuous positive airway pressure therapy (CPAP) or modafinil. All craniopharyngioma patients, with unexplained somnolence, were offered modafinil. RESULTS: Somnolence was reported by 20/28 (71·5%) craniopharyngioma patients and 4/23 (17%) obese subjects (P < 0·001). Median ESS was 7·5 (IQR 6, 10·7) in craniopharyngioma patients and 4·0 (4,8) in controls, P < 0·01. Eleven somnolent craniopharyngioma patients had obstructive sleep apnoea, in whom treatment led to a reduction in ESS by 6·4 ± 1·4, P = 0·01. Among the remaining nine patients, five were offered modafinil therapy, of whom four had benefit, three were not compliant with hormone replacement, and one died before intervention. There was no difference in the prevalence of obstructive sleep apnoea between craniopharyngioma (n = 13, 46%) and obese subjects (n = 14, 61%, P = 0·4). Body mass index (BMI) does not correlate with apnoea hypopnoea index [apnoea - hypopnoea index (AHI), r = 0·25, P = 0·08], which suggests that obesity alone does not explain the prevalence of sleep apnoea in craniopharyngioma patients. CONCLUSIONS: Somnolence is common in craniopharyngioma patients and in the majority is because of obstructive sleep apnoea. An additional group of somnolent craniopharyngioma patients benefits from modafinil.

Are there clinical features of a sensitized cough reflex?

Cough reflex hypersensitization is a key feature in patients with troublesome cough. The clinical consequence of this hypersensitive state is typified by bouts of coughing often triggered by low threshold stimuli encountered by the patient during normal daily activities including exposure to aerosols, scents and odours, a change in air temperature and when talking or laughing. These features are often perceived by cough patients to be the most disruptive aspect of their condition and undoubtedly contribute to impaired quality of life. Patients with troublesome cough may describe a range of additional symptoms and sensations including an 'urge to cough' or the feeling of an 'itch' at the back of the throat, or a choking sensation and occasionally chest pain or breathlessness. It is uncertain if these features arise due to the processes responsible for cough reflex sensitization or as a direct consequence of the underlying cough aetiology. In an attempt to understand the clinical features of a sensitized cough reflex, the spectrum of symptoms typically described by cough patients will be reviewed and possible underlying mechanisms considered. Since an intact cough reflex is crucial to airway protection, anti-tussive treatment that attenuates the hypersensitive cough state rather than abolishing the cough reflex completely would be preferable. Identifying such agents remains a clinical, scientific and pharmacological challenge.

Role of sphingosine 1-phosphate receptor expression in eosinophils of patients with allergic rhinitis, and effect of topical nasal steroid treatment on this receptor expression.

OBJECTIVE: Recent research has indicated that sphingosine 1-phosphate plays a role in allergy. This study examined the effect of allergen challenge on the expression of sphingosine 1-phosphate receptors on the eosinophils of allergic rhinitis patients, and the effect of steroid treatment on this expression. STUDY DESIGN: A prospective, non-randomised study. METHODS: The study had three parts. Firstly, sphingosine 1-phosphate receptor expression on the eosinophils of allergic rhinitis patients and control patients was determined. Secondly, sphingosine 1-phosphate receptor expression was quantified pre- and post-allergen challenge, before and after a short course of fluticasone propionate; all patients underwent symptom scoring and peak nasal inspiratory flow measurement pre- and post-allergen challenge, both before and after steroid or saline treatment. Thirdly, the effect of sphingosine 1-phosphate on eosinophil migration was examined. RESULTS: The eosinophils of both allergic rhinitis patients and controls expressed sphingosine 1-phosphate1, 3, 4, and 5. Eosinophils from all allergic rhinitis patients demonstrated up-regulation in sphingosine 1-phosphate expression after allergen challenge. These changes were statistically very significant for sphingosine 1-phosphate1, 4, and 5, and moderately significant for sphingosine 1-phosphate3. Sphingosine 1-phosphate receptor expression up-regulation was abolished in the steroid-treated group after allergen challenge; however, the saline-treated group showed no change in sphingosine 1-phosphate receptor expression after allergen challenge. Peak nasal inspiratory flow scores were significantly diminished after allergen challenge prior to treatment, but not after a course of topical nasal steroids. Sphingosine 1-phosphate induced eosinophil chemotaxis was increased following allergen challenge in allergic rhinitis subjects. CONCLUSIONS: Local intranasal steroid therapy acts directly to block allergen-induced up-regulation of sphingosine 1-phosphate receptors on the peripheral eosinophils of allergic rhinitis patients, and this is coincident with post-challenge peak nasal inspiratory flow measurement improvements. These observations support the idea that such an increase in sphingosine 1-phosphate receptor expression is clinically relevant in allergic rhinitis, with potential consequences for eosinophil migration and survival.

The Allergic Rhinitis and its Impact on Asthma system: a new classification of allergic rhinitis and nasal responsiveness.

OBJECTIVES AND HYPOTHESIS: Allergic rhinitis has traditionally been classified into seasonal and perennial rhinitis. However, many subjects with dual sensitisation do not fit neatly into either category. Recently, the Allergic Rhinitis and its Impact on Asthma workshop has proposed a new allergic rhinitis classification, into intermittent and persistent forms. The purpose of the present study was to investigate whether the symptomatic and secretory responsiveness of allergic rhinitis sufferers correlated well with the Allergic Rhinitis and its Impact on Asthma classification, compared with the traditional classification. STUDY DESIGN: Experimental study. METHODS: Forty subjects with allergic rhinitis and 13 normal controls underwent a unilateral nasal bradykinin challenge protocol. Symptom scores were recorded and secretion weights measured bilaterally using filter paper disks. The symptomatic and secretory responses of allergic subjects were analysed according to both the traditional and the Allergic Rhinitis and its Impact on Asthma classifications, and the two systems were compared. RESULTS: For both classification systems, the two groups of allergic subjects were clearly demarcated by secretory responses. However, after classification according to the traditional system, there was a lack of clear demarcation between the groups as regards symptomatic response, whereas clear demarcation of symptomatic responses was seen after using the Allergic Rhinitis and its Impact on Asthma classification. CONCLUSIONS: In allergic rhinitis subjects, the degree of nasal responsiveness was closely related to their Allergic Rhinitis and its Impact on Asthma classification. Furthermore, this classification was not compromised by the inclusion of subjects with dual sensitisation. Thus, the Allergic Rhinitis and its Impact on Asthma classification may have advantages for future research studies on allergic rhinitis.

Team Objective Structured Bedside Assessment (TOSBA): a novel and feasible way of providing formative teaching and assessment.

It can be challenging to teach and assess medical students successfully in the setting of a hospital ward using real patients. We describe a novel method of providing weekly formative clinical assessment and teaching to final year students on an acute medical ward: The Team Objective Structured Bedside Assessment (TOSBA). The TOSBA involves three groups of five students rotating through three ward-based stations (each station consists of an inpatient and facilitator). Each group spends 25 minutes at a bedside station where the facilitator asks consecutive students to perform one of five clinical tasks. Every student receives a standardised grade and is provided with educational feedback at each of the three stations. We report our 15-month experience using the TOSBA format to assess and teach a large number of medical students on a weekly basis. We discuss the advantages and potential drawbacks of our approach.

Recent consensus on the classification of rhinosinusitis--a way forward for research and practice?

Prior classification of rhinitis was into three categories: acute, subacute and chronic rhinosinusitis. The advantages of this classification were obvious but they were offset by some disadvantages. For example, the previous classification did not take account of the mechanisms underlying the condition or the clinical outcome. Hence, there was a need for evidence-based sinusitis classification guidelines. The American Academy of Otolaryngology-Head and Neck Surgery and other related societies published a classification of the condition and suggested clinical research strategies for patients with rhinosinusitis. The main conclusion was that sinusitis should be divided into four categories: acute (bacterial) rhinosinusitis, chronic rhinosinusitis (CRS) without polyps, CRS with polyps, and allergic fungal sinusitis. The aim of this current paper is to discuss the consensus for nomenclature, outline the proposed classification of different types of rhinosinusitis and to suggest some ways that we may audit these guidelines.

Screening for lung cancer using low dose CT scanning: results of 2 year follow up.

BACKGROUND: Screening with low dose chest computed tomographic scanning (LDCCT) may improve survival by identifying early asymptomatic lung cancer. METHODS: Four hundred and forty nine high risk subjects were screened with serial LDCCT scanning over 2 years. Fine needle aspiration biopsy was recommended for non-calcified nodules (NCNs) of >10 mm diameter or demonstrating interval growth. RESULTS: NCNs were identified in 111 subjects (24.7%), three of which were lung cancer. The overall prevalence (0.4%) and incidence (1.3%) rates of lung cancer detection were low. Three of the six lung cancers detected in the study were stage 1 non-small cell lung cancer; the remainder were unresectable central tumours. By contrast, eight subjects developed extrathoracic malignancy during the study period and other incidental pathology was noted in 221 subjects (49.2%). Smoking cessation rates at 19% were higher than in the general population, but 60.8% of subjects continued to smoke. CONCLUSION: LDCCT scanning is useful in detecting early peripheral non-small cell lung cancers but its usefulness as a screening tool is limited by low specificity and by poor sensitivity for central tumours.

Induction of nasal hyper-responsiveness by allergen challenge in allergic rhinitis: the role of afferent and efferent nerves.

BACKGROUND: Hyper-responsiveness of nasal secretory function and volume changes are features of allergic rhinitis (AR) that are mediated in part by neural mechanisms. The finding of nasal hyper-responsiveness in subjects with AR who are currently symptomatic, but not in those who are currently out of season and asymptomatic, suggests that induction of neural reflexes in allergic subjects occurs as a result of allergic inflammation. OBJECTIVES: To investigate whether allergen exposure in subjects with asymptomatic seasonal allergic rhinitis (SAR) may lead to induction of neural reflexes, and to investigate the components of the reflexes involved in this induction. METHODS: Asymptomatic subjects with (out-of-season) SAR underwent a nasal bradykinin challenge, before and 24 h after preceding ipsilateral (n = 11) and contralateral (n = 11) antigen challenge. Challenges were performed and nasal secretions collected using filter paper disks, and changes in nasal minimal cross-sectional area (A(min)) were measured using acoustic rhinometry. RESULTS: Preceding ipsilateral antigen challenge led to the induction of a contralateral secretory reflex (P = 0.01), which was absent in control experiments (P = 0.34). Ipsilateral secretion weights were also enhanced. Preceding contralateral antigen challenge also induced a contralateral secretory reflex (P = 0.03). Enhancement of the reduction in contralateral A(min) was also seen (P = 0.02). Ipsilateral responses were unchanged. CONCLUSIONS: Allergen exposure in asymptomatic allergic subjects leads to induction of neural reflexes, resulting in nasal hyper-responsiveness, which persists beyond the resolution of the acute allergic response. Our data suggest that the mechanisms of allergen-induced hyper-responsiveness involve both afferent and efferent components.

An alternative technique for nasal biopsy.

OBJECTIVES/HYPOTHESIS: The objective was to investigate the effectiveness of co-phenylcaine as a topical anesthetic agent for nasal mucosal biopsy. STUDY DESIGN: A prospective study. METHODS: Nasal mucosal biopsy specimens were taken from a site just anterior to the inferior turbinate following topical anesthesia with co-phenylcaine. All volunteers graded pain according to standard visual analogue scale (0-10) (VAS) scoring, and all were followed up after 24 hours for any epistaxis. RESULTS: Ninety nasal biopsy specimens were removed from 41 patients in all. Eight-two percent did not report any discomfort following this procedure (VAS score, 0). Ten patients reported mild discomfort (VAS scores ranging between, 1 and 3) and only six reported pain (VAS scores ranging from 5 to 7). However, five of these patients agreed to further biopsy and documented no discomfort during the repeat procedure. Only one patient required immediate intervention for hemorrhage after the procedure. In cases in which bleeding occurred (seven patients) it was documented within the first 6 hours, was minimal in content, and was controlled with local pressure. No systemic side effects were experienced. CONCLUSION: Co-phenylcaine is a suitable topical anesthetic agent for nasal mucosal biopsy. Removal of nasal tissue from a site anterior to the inferior turbinate can be performed under direct vision and provides sufficient tissue for histological assessment.

Screening for lung cancer using low dose CT scanning.

BACKGROUND: Lung cancer is the most common cause of cancer related death in Ireland. The majority of lung cancers are inoperable at the time of diagnosis and consequently the overall 5 year survival is less than 10%. The objective of the ProActive Lung Cancer Detection (PALCAD) study was to evaluate whether low dose chest computed tomographic scanning (LDCCT) can detect early stage asymptomatic lung cancer in a high risk urban population. METHODS: Four hundred and forty nine subjects of median age 55 years (range 50-74) with a median pack year smoking history of 45 years (range 10-160), with no previous cancer history and medically fit to undergo thoracic surgery were recruited. After informed consent, LDCCT was performed on all subjects. Non-calcified nodules (NCNs) of >/=10 mm in diameter were referred for biopsy. Follow up with interval LDCCT at 6, 12 and 24 months to exclude growth was recommended for NCNs <10 mm in diameter. RESULTS: Six (1.3%) NCNs of >/=10 mm were detected of which one (0.23%) had non-small cell lung cancer stage 1; 145 NCNs of <10 mm were detected in 87 (19.4%) subjects. Mediastinal masses were detected in three subjects (0.7%)-one small cell lung cancer and two benign duplication cysts. Incidental pathology was noted in 276 patients (61.5%), most commonly emphysema and coronary artery calcification. CONCLUSION: The prevalence of resectable lung cancer detected by LDCCT at baseline screening was low at 0.23%, but there was a high rate of significant incidental pathology.

An outreach programme for patients with an exacerbation of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is a common clinical condition characterised by airflow obstruction. The clinical course of the disease is characterised by intermittent exacerbations. In Ireland exacerbations of chronic obstructive pulmonary disease are a common cause of admission to acute medical hospitals. The Beaumont Hospital COPD Outreach Programme was designed to provide care at home for patients with an exacerbation of COPD that would otherwise require hospitalisation. Patients recruited to the programme were discharged home within 72 hours of admission and reviewed by the Outreach Team over a two week period. In addition to monitoring clinical progress the Team provided education, smoking cessation and medication advice. Analysis of the outcome of the first 100 patients recruited to the study show that one third of patients admitted to Hospital with an exacerbation of COPD are eligible for this programme and the average length of Hospital stay was 2.6 days. During the fourteen day follow up there was one death (non-respiratory) and six patients were re-admitted to hospital. Forty percent of smokers had abstained from smoking at the end of three months. In summary, the COPD Outreach programme is a safe and effective alternative to acute hospital care for selected patients with exacerbations of COPD.

Function of pulmonary neuronal M(2) muscarinic receptors in stable chronic obstructive pulmonary disease.

Anticholinergic drugs often cause a considerable degree of bronchodilation in patients with chronic obstructive pulmonary disease (COPD). Pulmonary neuronal M(2) muscarinic receptors function to limit the magnitude of vagally induced bronchoconstriction. We hypothesized that the effectiveness of anticholinergic agents in patients with COPD may reflect increased vagal reactivity due to dysfunction of M(2) muscarinic receptors. The function of M(2) receptors and the magnitude of vagally induced bronchoconstriction were assessed in subjects with normal lung function and in subjects with COPD. A nasal cold dry air challenge was used to induce a bronchoconstriction, measured as a change in airway resistance (Raw) at 5 Hz (R5) using impulse oscillometry. In subjects with COPD R5 rose from 0.68 +/- 0.06 to 0.74 +/- 0.07 kPa/L/s after the cold dry air challenge (p < 0.01) and in the control subjects R5 rose from 0.34 +/- 0.03 to 0.39 +/- 0.03 kPa/L/s (p < 0.01). The bronchoconstriction was inhibited by pretreatment with ipratropium bromide, indicating that it was vagally mediated. In both groups of subjects pretreatment with the selective M(2) muscarinic receptor agonist pilocarpine (5 mg/ml) prevented the cold air-induced bronchoconstriction, indicating normal function of M(2) receptors. These studies indicate that M(2) muscarinic receptors are functional in subjects with stable COPD.

Eosinophils and airway nerves in asthma.

In the lungs, neuronal M2 muscarinic receptors limit the release of acetylcholine from postganglionic cholinergic nerves. However, these receptors are not functional under certain circumstances in animal models of hyperreactivity such as occurs after exposure of sensitised animals to an allergen or during a respiratory tract virus infection. This loss of M2 receptor function leads to an increase in acetylcholine release from cholinergic nerves and thus is a mechanism for the vagally mediated hyperreactivity seen in these animals. Studies in animal models of hyperreactivity have shown that eosinophils localise to the airway nerves of sensitised animals after antigen challenge. Inhibiting this localisation of eosinophils either with an antibody to the eosinophil survival cytokine IL-5 or the eosinophil adhesion molecule VLA-4 prevents loss of M2 muscarinic receptor function. It is likely that eosinophil MBP is responsible for the loss of M2 receptor function, since inhibiting eosinophil MBP with an antibody or neutralising MBP with heparin prevents this loss of function. These data are also supported by ligand binding studies where it has been shown that eosinophil MBP is an allosteric antagonist at neuronal M2 muscarinic receptors. Loss of function of lung neuronal M2 muscarinic receptors may also occur under certain circumstances in patients with asthma, although the mechanisms are not yet established.

Substance P-induced airway hyperreactivity is mediated by neuronal M(2) receptor dysfunction.

Neuronal muscarinic (M(2)) receptors inhibit release of acetylcholine from the vagus nerves. Hyperreactivity in antigen-challenged guinea pigs is due to blockade of these M(2) autoreceptors by eosinophil major basic protein (MBP) increasing the release of acetylcholine. In vivo, substance P-induced hyperactivity is vagally mediated. Because substance P induces eosinophil degranulation, we tested whether substance P-induced hyperreactivity is mediated by release of MBP and neuronal M(2) receptor dysfunction. Pathogen-free guinea pigs were anesthetized and ventilated. Thirty minutes after intravenous administration of [Sar(9),Met(O(2))(11)]- substance P, guinea pigs were hyperreactive to vagal stimulation and M(2) receptors were dysfunctional. The depletion of inflammatory cells with cyclophosphamide or the administration of an MBP antibody or a neurokinin-1 (NK(1)) receptor antagonist (SR-140333) all prevented substance P-induced M(2) dysfunction and hyperreactivity. Intravenous heparin acutely reversed M(2) receptor dysfunction and hyperreactivity. Thus substance P releases MBP from eosinophils resident in the lungs by stimulating NK(1) receptors. Substance P-induced hyperreactivity is mediated by blockade of inhibitory neuronal M(2) receptors by MBP, resulting in increased release of acetylcholine.