Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children.

BACKGROUND: Regional anaesthesia may reduce the rate of persistent postoperative pain (PPP), a frequent and debilitating condition. This review was originally published in 2012 and updated in 2017. OBJECTIVES: To compare local anaesthetics and regional anaesthesia versus conventional analgesia for the prevention of PPP beyond three months in adults and children undergoing elective surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to December 2016 without any language restriction. We used a combination of free text search and controlled vocabulary search. We limited results to randomized controlled trials (RCTs). We updated this search in December 2017, but these results have not yet been incorporated in the review. We conducted a handsearch in reference lists of included studies, review articles and conference abstracts. We searched the PROSPERO systematic review registry for related systematic reviews. SELECTION CRITERIA: We included RCTs comparing local or regional anaesthesia versus conventional analgesia with a pain outcome beyond three months after elective, non-orthopaedic surgery. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trial quality and extracted data and adverse events. We contacted study authors for additional information. We presented outcomes as pooled odds ratios (OR) with 95% confidence intervals (95% CI), based on random-effects models (inverse variance method). We analysed studies separately by surgical intervention, but pooled outcomes reported at different follow-up intervals. We compared our results to Bayesian and classical (frequentist) models. We investigated heterogeneity. We assessed the quality of evidence with GRADE. MAIN RESULTS: In this updated review, we identified 40 new RCTs and seven ongoing studies. In total, we included 63 RCTs in the review, but we were only able to synthesize data on regional anaesthesia for the prevention of PPP beyond three months after surgery from 39 studies, enrolling a total of 3027 participants in our inclusive analysis.Evidence synthesis of seven RCTs favoured epidural anaesthesia for thoracotomy, suggesting the odds of having PPP three to 18 months following an epidural for thoracotomy were 0.52 compared to not having an epidural (OR 0.52 (95% CI 0.32 to 0.84, 499 participants, moderate-quality evidence). Simlarly, evidence synthesis of 18 RCTs favoured regional anaesthesia for the prevention of persistent pain three to 12 months after breast cancer surgery with an OR of 0.43 (95% CI 0.28 to 0.68, 1297 participants, low-quality evidence). Pooling data at three to 8 months after surgery from four RCTs favoured regional anaesthesia after caesarean section with an OR of 0.46, (95% CI 0.28 to 0.78; 551 participants, moderate-quality evidence). Evidence synthesis of three RCTs investigating continuous infusion with local anaesthetic for the prevention of PPP three to 55 months after iliac crest bone graft harvesting (ICBG) was inconclusive (OR 0.20, 95% CI 0.04 to 1.09; 123 participants, low-quality evidence). However, evidence synthesis of two RCTs also favoured the infusion of intravenous local anaesthetics for the prevention of PPP three to six months after breast cancer surgery with an OR of 0.24 (95% CI 0.08 to 0.69, 97 participants, moderate-quality evidence).We did not synthesize evidence for the surgical subgroups of limb amputation, hernia repair, cardiac surgery and laparotomy. We could not pool evidence for adverse effects because the included studies did not examine them systematically, and reported them sparsely. Clinical heterogeneity, attrition and sparse outcome data hampered evidence synthesis. High risk of bias from missing data and lack of blinding across a number of included studies reduced our confidence in the findings. Thus results must be interpreted with caution. AUTHORS' CONCLUSIONS: We conclude that there is moderate-quality evidence that regional anaesthesia may reduce the risk of developing PPP after three to 18 months after thoracotomy and three to 12 months after caesarean section. There is low-quality evidence that regional anaesthesia may reduce the risk of developing PPP three to 12 months after breast cancer surgery. There is moderate evidence that intravenous infusion of local anaesthetics may reduce the risk of developing PPP three to six months after breast cancer surgery.Our conclusions are considerably weakened by the small size and number of studies, by performance bias, null bias, attrition and missing data. Larger, high-quality studies, including children, are needed. We caution that except for breast surgery, our evidence synthesis is based on only a few small studies. On a cautionary note, we cannot extend our conclusions to other surgical interventions or regional anaesthesia techniques, for example we cannot conclude that paravertebral block reduces the risk of PPP after thoracotomy. There are seven ongoing studies and 12 studies awaiting classification that may change the conclusions of the current review once they are published and incorporated.

Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children.

BACKGROUND: Regional anaesthesia may reduce the rate of persistent postoperative pain (PPP), a frequent and debilitating condition. This review was originally published in 2012 and updated in 2017. OBJECTIVES: To compare local anaesthetics and regional anaesthesia versus conventional analgesia for the prevention of PPP beyond three months in adults and children undergoing elective surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to December 2016 without any language restriction. We used a combination of free text search and controlled vocabulary search. We limited results to randomized controlled trials (RCTs). We updated this search in December 2017, but these results have not yet been incorporated in the review. We conducted a handsearch in reference lists of included studies, review articles and conference abstracts. We searched the PROSPERO systematic review registry for related systematic reviews. SELECTION CRITERIA: We included RCTs comparing local or regional anaesthesia versus conventional analgesia with a pain outcome beyond three months after elective, non-orthopaedic surgery. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trial quality and extracted data and adverse events. We contacted study authors for additional information. We presented outcomes as pooled odds ratios (OR) with 95% confidence intervals (95% CI), based on random-effects models (inverse variance method). We analysed studies separately by surgical intervention, but pooled outcomes reported at different follow-up intervals. We compared our results to Bayesian and classical (frequentist) models. We investigated heterogeneity. We assessed the quality of evidence with GRADE. MAIN RESULTS: In this updated review, we identified 40 new RCTs and seven ongoing studies. In total, we included 63 RCTs in the review, but we were only able to synthesize data on regional anaesthesia for the prevention of PPP beyond three months after surgery from 41 studies, enrolling a total of 3143 participants in our inclusive analysis.Evidence synthesis of seven RCTs favoured epidural anaesthesia for thoracotomy, suggesting the odds of having PPP three to 18 months following an epidural for thoracotomy were 0.52 compared to not having an epidural (OR 0.52 (95% CI 0.32 to 0.84, 499 participants, moderate-quality evidence). Simlarly, evidence synthesis of 18 RCTs favoured regional anaesthesia for the prevention of persistent pain three to 12 months after breast cancer surgery with an OR of 0.43 (95% CI 0.28 to 0.68, 1297 participants, low-quality evidence). Pooling data at three to 8 months after surgery from four RCTs favoured regional anaesthesia after caesarean section with an OR of 0.46, (95% CI 0.28 to 0.78; 551 participants, moderate-quality evidence). Evidence synthesis of three RCTs investigating continuous infusion with local anaesthetic for the prevention of PPP three to 55 months after iliac crest bone graft harvesting (ICBG) was inconclusive (OR 0.20, 95% CI 0.04 to 1.09; 123 participants, low-quality evidence). However, evidence synthesis of two RCTs also favoured the infusion of intravenous local anaesthetics for the prevention of PPP three to six months after breast cancer surgery with an OR of 0.24 (95% CI 0.08 to 0.69, 97 participants, moderate-quality evidence).We did not synthesize evidence for the surgical subgroups of limb amputation, hernia repair, cardiac surgery and laparotomy. We could not pool evidence for adverse effects because the included studies did not examine them systematically, and reported them sparsely. Clinical heterogeneity, attrition and sparse outcome data hampered evidence synthesis. High risk of bias from missing data and lack of blinding across a number of included studies reduced our confidence in the findings. Thus results must be interpreted with caution. AUTHORS' CONCLUSIONS: We conclude that there is moderate-quality evidence that regional anaesthesia may reduce the risk of developing PPP after three to 18 months after thoracotomy and three to 12 months after caesarean section. There is low-quality evidence that regional anaesthesia may reduce the risk of developing PPP three to 12 months after breast cancer surgery. There is moderate evidence that intravenous infusion of local anaesthetics may reduce the risk of developing PPP three to six months after breast cancer surgery.Our conclusions are considerably weakened by the small size and number of studies, by performance bias, null bias, attrition and missing data. Larger, high-quality studies, including children, are needed. We caution that except for breast surgery, our evidence synthesis is based on only a few small studies. On a cautionary note, we cannot extend our conclusions to other surgical interventions or regional anaesthesia techniques, for example we cannot conclude that paravertebral block reduces the risk of PPP after thoracotomy. There are seven ongoing studies and 12 studies awaiting classification that may change the conclusions of the current review once they are published and incorporated.

Swallowed Fluticasone Propionate Is an Effective Long-Term Maintenance Therapy for Children With Eosinophilic Esophagitis.

OBJECTIVES: Although effective in the treatment of eosinophilic esophagitis (EoE) in children, limited data exist on long-term safety and efficacy of swallowed topical corticosteroids. We investigated whether long-term use of swallowed fluticasone in children with EoE leads to sustained reduction in esophageal eosinophils, and endoscopic and clinical improvement. METHODS: In an open-label, prospective, single-center study, we offered pediatric patients with active EoE fluticasone 2 puffs to swallow twice a day (strengths in µg/puff: 2-4 years: 44, 5-11 years: 110, ≥12 years: 220). Clinical, endoscopic, and histological assessments were performed at baseline and shortly after therapy. If histological remission was seen, fluticasone was continued with clinical follow-ups every 4 months and endoscopic and histological follow-ups yearly. Clinical scores were derived from eight symptoms (abdominal pain, nausea, vomiting, regurgitation, chest pain, dysphagia, food impaction, and early satiety). Endoscopic scores were derived from six features (rings, exudates, furrows, edema, stricture, and shearing). Scores were expressed as ratio (features present/total). In addition to peak eosinophils/high power field (HPF) (primary outcome), histological features (eosinophilic microabscesses, degranulation, superficial layering, basal zone hyperplasia, dilated intercellular spaces, and lamina propria fibrosis) were assessed. Median clinical and endoscopic scores and individual histologic features were compared over 4 time intervals: <4 months, 4-12 months, 13-24 months, and >24 months. Growth and adverse effects were monitored. RESULTS: We enrolled 54 patients, 80% male, median age 6.5 years (range 2-17 years), 85% atopic (57% asthma, 68% allergic rhinitis, and 31% atopic dermatitis), and 74% with food allergy. Mean follow-up was 20.4 months, the longest being 68 months (5.7 years). Esophageal eosinophil counts significantly decreased (median peak eosinophils/HPF at baseline 72, <4 months: 0.5, 4-12 months: 1.75, 13-24 months: 10, and >24 months: 12, all P<0.01). All histological features significantly decreased from baseline to all follow-up time points (all P<0.01). Lamina propria fibrosis significantly decreased (% patients with fibrosis at baseline 92, <4 months: 41, 4-12 months: 50, 13-24 months: 45, and >24 months: 39, all P<0.01). Endoscopic features improved (score at baseline 0.37, <4 months: 0.17, 4-12 months: 0.17, 13-24 months: 0, and >24 months: 0.1, all P<0.01, except at >24 months: P<0.05). Symptoms improved (score at baseline 0.22, <4 months: 0, 4-12 months: 0.11, 13-24 months: 0.11, and >24 months: 0.11, all P<0.05 except at >24 months: P=0.05). In a mixed linear regression model that accounts for correlation of repeated observations in the patient in a per-patient analysis, we found that treatment with swallowed fluticasone led to a statistically significant and sustained decrease in peak esophageal eosinophil counts. Asymptomatic esophageal candidiasis was seen in three children but resolved with anti-fungal therapy. Height and weight z-scores followed expected growth curves. CONCLUSIONS: We demonstrate that swallowed fluticasone is effective as a long-term maintenance therapy for children with EoE, without growth impediment or serious side effects.

Food Allergy.

Food allergy is a growing health problem affecting both pediatric and adult patients. Food allergies are often immunoglobulin E (IgE) mediated but other food-induced non-IgE-mediated diseases exist. Diagnosis of food allergy relies on the combination of clinical and reaction history, skin and IgE testing as well as oral food challenges. Although oral immunotherapy has been able to achieve sustained unresponsiveness in some patients, no cure for food allergies has been found to date. Avoidance of the inciting food as well as availability of epinephrine autoinjectors remains the mainstay of treatment.

The physician experience of patient to provider prejudice (PPtP).

Background: Patients can demonstrate prejudice and bias toward minoritized physicians in a destructive dynamic identified as PPtP (Patient Prejudice toward Providers). These interactions have a negative impact on the physical and mental well-being of both those who are targeted and those who witness such behaviors. Study purpose: The purpose of this study was to explore the PPtP experiences of attending physicians who identify as a minority based on race, ethnicity, citizenship status, or faith preference. Methods: Qualitative methodology was used to collect data using in-depth interviews. 15 attending physicians (8 male, 7 female, aged 33-55 years) who identified as minorities based on ethnicity, citizenship status, or faith practices were interviewed individually. Interviews were conducted using a guide validated in previous studies and content analysis was performed by two trained researchers to identify themes. Results: Five themes were identified: A Continuum of Offenses, Professional Growth through Adversity, Organizational Issues, Role of Colleagues, and Consequences for Provision of Care. Findings suggest that although attending physicians learned to cope with PPtP, the experience of being treated with bias negatively impacted their well-being and work performance. Attending physicians also felt that white majority medical students sometimes treated them with prejudice but expressed a commitment to protecting vulnerable trainees from PPtP. Conclusion: The experience of PPtP occurs consistently throughout a career in medicine, often beginning in the years of training and persisting into the phase of attending status. This makes it imperative to include strategies that address PPtP in order to successfully recruit and retain minoritized physicians.

Food Allergy.

Food allergy is a growing health problem affecting both pediatric and adult patients. Food allergies are often immunoglobulin E (IgE) mediated but other food-induced non-IgE-mediated diseases exist. Diagnosis of food allergy relies on the combination of clinical and reaction history, skin and IgE testing as well as oral food challenges. Although oral immunotherapy has been able to achieve sustained unresponsiveness in some patients, no cure for food allergies has been found to date. Avoidance of the inciting food as well as availability of epinephrine autoinjectors remains the mainstay of treatment.

Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery.

BACKGROUND: Regional anaesthesia may reduce the rate of persistent (chronic) pain after surgery, a frequent and debilitating condition. OBJECTIVES: To compare local anaesthetics and regional anaesthesia versus conventional analgesia for the prevention of persistent pain six or 12 months after surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), PubMed (1966 to April 2012), EMBASE (1966 to May 2012) and CINAHL (1966 to May 2012) without any language restriction. We used a combination of free text search and controlled vocabulary search. The results were limited to randomized controlled clinical trials (RCTs). We conducted a handsearch in reference lists of included trials, review articles and conference abstracts. SELECTION CRITERIA: We included RCTs comparing local anaesthetics or regional anaesthesia versus conventional analgesia with a pain outcome at six or 12 months after surgery. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data, including information on adverse events. We contacted study authors for additional information. Results are presented as pooled odds ratios (OR) with 95% confidence intervals (CI), based on random-effects models (inverse variance method). We grouped studies according to surgical interventions. We employed the Chi(2) test and calculated the I(2) statistic to investigate study heterogeneity. MAIN RESULTS: We identified 23 RCTs studying local anaesthetics or regional anaesthesia for the prevention of persistent (chronic) pain after surgery. Data from a total of 1090 patients with outcomes at six months and of 441 patients with outcomes at 12 months were presented. No study included children. We pooled data from 250 participants after thoracotomy, with outcomes at six months. Data favoured regional anaesthesia for the prevention of chronic pain at six months after thoracotomy with an OR of 0.33 (95% CI 0.20 to 0.56). We pooled two studies on paravertebral block for breast cancer surgery; the pooled data of 89 participants with outcomes at five to six months favoured paravertebral block with an OR of 0.37 (95% CI 0.14 to 0.94).The methodological quality of the included studies was intermediate. Adverse effects were not studied systematically and were reported sparsely. Clinical heterogeneity, attrition and sparse outcome data hampered the assessment of effects, especially at 12 months. AUTHORS' CONCLUSIONS: Epidural anaesthesia may reduce the risk of developing chronic pain after thoracotomy in about one patient out of every four patients treated. Paravertebral block may reduce the risk of chronic pain after breast cancer surgery in about one out of every five women treated. Our conclusions are significantly weakened by performance bias, shortcomings in allocation concealment, considerable attrition and incomplete outcome data. We caution that our evidence synthesis is based on only a few, small studies. More studies with high methodological quality, addressing various types of surgery and different age groups, including children, are needed.

The Impact of Patient Prejudice on Minoritized Female Physicians.

Background: Patient bias and prejudice directed against physicians from diverse backgrounds is a frequent occurrence in healthcare. Female physicians have long experienced discrimination in the healthcare system based on their gender alone. The dynamic known as Patient Prejudice toward Providers (PPtP) is disproportionately affecting female physicians because it is frequently compounded by sexism. Aim: The goal of this study was to explore the impact of PPtP on female resident and attending physicians. Methods: Using transcribed one-on-one interviews from a larger study of PPtP affecting resident and attending physicians, ten interviews with female physicians (resident and attending) from diverse ethnic backgrounds and countries of training at a large academic medical center were analyzed. The authors independently reviewed the interviews using an iterative process within and across interviews to inductively identify repeating words, phrases, and concepts relevant to the study aim. Results: Demographics of the ten participants included age (mean 34.6 years), ethnicity (6 Asian, 2 Hispanic, 2 African), and country of training (10% IMG vs. 90% US trained). Four of the interviewees were residents and six were attendings. Themes that emerged from the analysis included experiencing "A Gendered Continuum of Abuse," "Establishing a Higher Standard of Competency," "Overcoming the Stereotype of the White Male Physician," "The Physicality of Self Identity," and "The Need to be Protective of Minoritized Trainees." All participants agreed that these perceptions created an adverse environment at the workplace and impacted on patient care. Conclusions: Discrimination of physicians based on their gender or their race/ethnicity has been reported. This study highlights the compounded effects of patient prejudice on female minoritized physicians. Organizations and individuals should identify and implement strategies to address the impact of PPtP and sexism in order to create an environment where all women can thrive professionally.

Identification of IgE sequential epitopes of lentil (Len c 1) by means of peptide microarray immunoassay.

BACKGROUND: Lentils are often responsible for allergic reactions to legumes in Mediterranean children. Although the primary sequence of the major allergen Len c 1 is known, the location of the IgE-binding epitopes remains undefined. OBJECTIVE: We sought to identify IgE-binding epitopes of Len c 1 and relate epitope binding to clinical characteristics. METHODS: One hundred thirty-five peptides corresponding to the primary sequence of Len c 1 were probed with sera from 33 patients with lentil allergy and 15 nonatopic control subjects by means of microarray immunoassay. Lentil-specific IgE levels, skin prick test responses, and clinical reactions to lentil were determined. Epitopes were defined as overlapping signal above interslide and intraslide cutoffs and confirmed by using inhibition assays with a peptide from the respective region. Hierarchic clustering of microarray data was used to correlate binding patterns with clinical findings. RESULTS: The patients with lentil allergy specifically recognized IgE-binding epitopes located in the C-terminal region between peptides 107 and 135. Inhibition experiments confirmed the specificity of IgE binding in this region, identifying different epitopes. Linkage of cluster results with clinical data and lentil-specific IgE levels displayed a positive correlation between lentil-specific IgE levels, epitope recognition, and respiratory symptoms. Modeling based on the 3-dimensional structure of a homologous soy vicilin suggests that the Len c 1 epitopes identified are exposed on the surface of the molecule. CONCLUSION: Several IgE-binding sequential epitopes of Len c 1 have been identified. Epitopes are located in the C-terminal region and are predicted to be exposed on the surface of the protein. Epitope diversity is positively correlated with IgE levels, pointing to a more polyclonal IgE response.

Development of a novel peptide microarray for large-scale epitope mapping of food allergens.

BACKGROUND: The peptide microarray is a novel assay that facilitates high-throughput screening of peptides with a small quantity of sample. OBJECTIVE: We sought to use overlapping peptides of milk allergenic proteins as a model system to establish a reliable and sensitive peptide microarray-based immunoassay for large-scale epitope mapping of food allergens. METHODS: A milk peptide microarray was developed by using commercially synthesized peptides (20-mers, 3 offset) covering the primary sequences of alpha(s1)-casein, alpha(s2)-casein, beta-casein, kappa-casein, and beta-lactoglobulin. Conditions for printing and immunolabeling were optimized using a serum pool of 5 patients with milk allergy. Reproducibility of the milk peptide microarray was evaluated using replicate arrays immunolabeled with the serum pool, whereas specificity and sensitivity were assessed by using serial dilution of the serum pool and a peptide inhibition assay. RESULTS: Our results show that epitopes identified by the peptide microarray were mostly consistent with those identified previously by SPOT membrane technology, but with specific binding to a few newly identified epitopes of milk allergens. Data from replicate arrays were reproducible (r > or = 0.92) regardless of printing lots, immunolabeling, and serum pool batches. Using the serially diluted serum pool, we confirmed that IgE antibody binding detected in the array was specific. Peptide inhibition of IgE binding to the same peptide and overlapping peptides further confirmed the specificity of the array. CONCLUSION: A reliable peptide microarray was established for large-scale IgE epitope mapping of milk allergens, and this robust technology could be applied for epitope mapping of other food allergens.

Local anesthetics and regional anesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children: A Cochrane systematic review and meta-analysis update.

BACKGROUND: Regional anesthesia may mitigate the risk of persistent postoperative pain (PPP). This Cochrane review, published originally in 2012, was updated in 2017. METHODS: We updated our search of Cochrane CENTRAL, PubMed, EMBASE and CINAHL to December 2017. Only RCTs investigating local anesthetics (by any route) or regional anesthesia versus any combination of systemic (opioid or non-opioid) analgesia in adults or children, reporting any pain outcomes beyond three months were included. Data were extracted independently by at least two authors, who also appraised methodological quality with Cochrane 'Risk of bias' assessment and pooled data in surgical subgroups. We pooled studies across different follow-up intervals. As summary statistic, we reported the odds ratio (OR) with 95% confidence intervals and calculated the number needed to benefit (NNTB). We considered classical, Bayesian alternatives to our evidence synthesis. We explored heterogeneity and methodological bias. RESULTS: 40 new and seven ongoing studies, identified in this update, brought the total included RCTs to 63. We were only able to synthesize data from 39 studies enrolling 3027 participants in a balanced design. Evidence synthesis favored regional anesthesia for thoracotomy (OR 0.52 [0.32 to 0.84], moderate-quality evidence), breast cancer surgery (OR 0.43 [0.28 to 0.68], low-quality evidence), and cesarean section (OR 0.46, [0.28 to 0.78], moderate-quality evidence). Evidence synthesis favored continuous infusion of local anesthetic after breast cancer surgery (OR 0.24 [0.08 to 0.69], moderate-quality evidence), but was inconclusive after iliac crest bone graft harvesting (OR 0.20, [0.04 to 1.09], low-quality evidence). CONCLUSIONS: Regional anesthesia reduces the risk of PPP. Small study size, performance, null, and attrition bias considerably weakened our conclusions. We cannot extrapolate to other interventions or to children.

Dopamine D2 receptor mRNA expression is increased in the jugular-nodose ganglia of rats with nitrogen dioxide-induced chronic bronchitis.

The bronchodilatatory effect of inhaled dopamine or dopamine D(2) receptor agonists in cases of bronchial constriction may involve the suppression of pathologically increased airway sensory nerve activity. The aim of this study is to investigate the regulation of the dopamine D(2) receptor mRNA expression in the ganglia of rats with nitrogen dioxide-induced chronic bronchitis compared with that in ganglia of healthy control animals. Rats were exposed to nitrogen dioxide (10 ppm, 20 d) and dopamine D(2) receptor mRNA levels in sensory ganglia (jugular-nodose, trigeminal, cervical dorsal root and thoracic dorsal root ganglia) were examined by quantitative real-time polymerase chain reaction and compared to control tissues. Whereas for trigeminal and dorsal root ganglia the dopamine D(2) receptor expression levels showed no difference between both animal groups, there was a significant (p<0.05) increase in the jugular-nodose ganglia with a 2.1-fold factor. The increase of dopamine D(2) receptor mRNA in jugular-nodose sensory neurons which innervate the airways may represent a neurochemical basis for the effects seen in man and animal models following topical administration of dopamine or dopamine agonists onto the respiratory epithelium.