The impact of implementing an endocarditis team in comparison to the classic heart team in a tertiary referral centre.

BACKGROUND: Infective endocarditis (IE) is a complex disease for which the European Society of Cardiology guideline recommends a dedicated multidisciplinary endocarditis team (ET) approach since 2015. It is currently unknown whether this ET approach is beneficial compared to a classic heart team approach including bedside consultation by an infectious disease specialist in Western Europe. METHODS: This retrospective single centre, observational cohort study was conducted at the Radboudumc, a tertiary referral centre in the Netherlands. Consecutive patients treated for IE were included from September 2017 to September 2018 before implementation of a dedicated ET and from May 2019 to May 2020 afterwards. RESULTS: In total, 90 IE patients (45 patients before and 45 patients after the implementation of the ET) were included. No significant differences were found in diagnostic workup, surgical treatment (surgery performed 69% vs. 71%, p = 0.82), time to surgery because of an urgent indication (median 4 vs. 6 days, p = 0.82), in-hospital complications (53% vs. 67%, p = 0.20), and 6-month mortality (11% vs. 13%, p = 0.75) between IE patients treated before and after the implementation of the ET. CONCLUSION: Formalization of the recommended multidisciplinary endocarditis team might not significantly improve the complication rate nor the short term outcome.

High body mass index and pre-existing autoimmune disease are associated with an increased risk of immune-related adverse events in cancer patients treated with PD-(L)1 inhibitors across different solid tumors.

BACKGROUND: Treatment with anti-PD-(L)1 antibodies, approved for several oncology indications, can lead to immune-related adverse events (irAEs). We aimed to investigate risk factors associated with an increased reporting of irAEs in patients treated with PD-(L)1 inhibitors approved for solid tumor indications. PATIENTS AND METHODS: A retrospective review was performed of individual data from patients in phase II/III registrational studies for PD-(L)1 inhibitors in solid tumors. Data on baseline characteristics and adverse events were extracted. Univariate and multivariable logistic regression models were used to identify risk factors. RESULTS: In total, 5123 patients were included from 15 studies reporting on the use of four PD-(L)1 inhibitors for five solid tumor indications. Univariate analysis suggested that type of study drug (P < 0.001), indication (P = 0.003), body mass index (BMI) (P = 0.001), and baseline autoimmune disease (P < 0.001) were associated with an increased occurrence of any irAE. Using logistic regression analyses, three factors were identified as increasing the risk of irAE: BMI ≥ 30 kg/m2 [odds ratio (OR) 1.5, 95% confidence interval (CI) 1.2-1.8] in comparison to normal BMI, having an autoimmune disease at baseline (OR 1.8, 95% CI 1.1-2.7), and use of a PD-L1 inhibitor (OR 1.6, 95% CI 1.2-2.0). The latter finding is probably biased due to the selection of the studies in the dataset with complete information on baseline characteristics. CONCLUSION: This study was conducted using a large dataset of individual patient data from clinical trials comprising multiple solid tumor indications. We demonstrated that patients with obesity and concurrent autoimmune disease were at increased risk of developing irAEs.

Effect of early nutritional intake on long-term growth and bone mineralization of former very low birth weight infants.

BACKGROUND: Preterm infants are at risk for impaired bone mineralization and growth in length later in life due to inadequate nutritional intake in the early postnatal period. OBJECTIVE: To investigate whether increased nutritional supplementation of calcium, phosphate and protein in Very Low Birth Weight (VLBW) infants during the first 14days after birth was associated with improvement in length and bone development until 9-10years of age. DESIGN: Observational follow-up study of VLBW infants (birth weight<1500g or gestational age<32weeks) born in two consecutive years (eligible infants: 2004 n: 63 and 2005: n: 66). Cohort 2005 received higher intake of calcium, phosphate and protein with parenteral nutrition compared to Cohort 2004. Anthropometric data were collected during standard follow-up visits until five years, and additionally at 9-10years of age including measurements of bone mineral content, bone mineral density of the whole body and lumbar spine determined by dual-energy X-ray absorptiometry. Long-term growth trajectories of both cohorts were evaluated separately for participants born appropriate (AGA) and small for gestational age (SGA), stratified by gender. Multivariate linear regression was used to examine the effect of nutritional intake and clinical covariates on length and bone mineralization. RESULTS: Both cohorts achieved a catch-up in length to SDS within the normal range by 6months (length SDS: estimated mean (95% confidence interval (CI): 6months: Cohort 2004: -0.7 (-1.1, -0.3) Cohort 2005: -0.5 (-0.8, -0.2)). Bone mineral content and density were within the normal range and not different between the cohorts. SGA children achieved a catch-up in length at 5years with bone mineralization comparable to AGA children. Only for girls birth weight was significantly associated with length SDS (per gram: ß 0.001; 95% CI (0.000, 0.003); p=0.03) There was no evidence of an association between early nutritional intake and bone mineralization. CONCLUSION: Children born as appropriate or small for gestational age preterm infants are able to catch up in length after the postnatal period, and achieve a normal length and bone mineralization at age nine-ten years. An improvement of calcium and phosphate intake during the first 14days after birth was not associated with improvement in length and bone development.

Adolescent mental health and behavioural predictors of being NEET: a prospective study of young adults not in employment, education, or training.

BACKGROUND: Young adults who are not in employment, education, or training (NEET) are at risk of long-term economic disadvantage and social exclusion. Knowledge about risk factors for being NEET largely comes from cross-sectional studies of vulnerable individuals. Using data collected over a 10-year period, we examined adolescent predictors of being NEET in young adulthood. METHODS: We used data on 1938 participants from the Victorian Adolescent Health Cohort Study, a community-based longitudinal study of adolescents in Victoria, Australia. Associations between common mental disorders, disruptive behaviour, cannabis use and drinking behaviour in adolescence, and NEET status at two waves of follow-up in young adulthood (mean ages of 20.7 and 24.1 years) were investigated using logistic regression, with generalised estimating equations used to account for the repeated outcome measure. RESULTS: Overall, 8.5% of the participants were NEET at age 20.7 years and 8.2% at 24.1 years. After adjusting for potential confounders, we found evidence of increased risk of being NEET among frequent adolescent cannabis users [adjusted odds ratio (ORadj) = 1.74; 95% confidence interval (CI) 1.10-2.75] and those who reported repeated disruptive behaviours (ORadj = 1.71; 95% CI 1.15-2.55) or persistent common mental disorders in adolescence (ORadj = 1.60; 95% CI 1.07-2.40). Similar associations were present when participants with children were included in the same category as those in employment, education, or training. CONCLUSIONS: Young people with an early onset of mental health and behavioural problems are at risk of failing to make the transition from school to employment. This finding reinforces the importance of integrated employment and mental health support programmes.

Evaluating the success of a marine protected area: A systematic review approach.

Marine Protected Areas (MPAs), marine areas in which human activities are restricted, are implemented worldwide to protect the marine environment. However, with a large proportion of these MPAs being no more than paper parks, it is important to be able to evaluate MPA success, determined by improvements to biophysical, socio-economic and governance conditions. In this study a systematic literature review was conducted to determine the most frequently used indicators of MPA success. These were then applied to a case study to demonstrate how success can be evaluated. The fifteen most frequently used indicators included species abundance, level of stakeholder participation and the existence of a decision-making and management body. Using the indicator framework with a traffic light system, we demonstrate how an MPA can be evaluated in terms of how well it performs against the indicators using secondary data from the literature. The framework can be used flexibly. For example, where no MPA data currently exist, the framework can be populated by qualitative data provided by local stakeholder knowledge. This system provides a cost-effective and straightforward method for managers and decision-makers to determine the level of success of any MPA and identify areas of weakness. However, given the variety of motivations for MPA establishment, this success needs to be determined in the context of the original management objectives of the MPA with greater weighting being placed on those objectives where appropriate.

Pelvic exenteration for recurrent squamous cell carcinoma of the pelvic organs arising from the cloaca--a single institution's experience over 16 years.

AIM: Minimal data are available on the role of pelvic exenteration in patients with recurrent squamous cell carcinoma (SCC) of the pelvic organs. This study aimed to highlight our experience of pelvic exenteration in patients with recurrent and re-recurrent SCC of the pelvic organs. METHOD: A retrospective review of all patients who underwent pelvic exenteration for recurrent SCC of the pelvic organs arising from the embryological cloaca from 1994 to 2010 was performed. RESULTS: Twenty-four patients (median age 59, range, 27-79 years) underwent pelvic exenteration for recurrent SCC of the anus (18), cervix and upper vagina (2), lower vagina (1) and the vulva (3). Nine patients with anal SCC had undergone abdominoperineal excision prior to pelvic exenteration. Ten (41.7%) patients underwent a complete pelvic exenteration procedure, while sacrectomy was performed in 13 (54.2%) patients. There was no 30-day inpatient mortality. An R0 resection was achieved in 15 (62.5%) patients. Three (12.5%) had R1 resections while 6 (25%) had R2 resections. In the 15 patients with an R0 resection, 7 (46.7%) developed metastatic disease at a median of 18 (range 10-131) months. After a median follow-up of 26 (range 4-169) months, 1- and 2-year overall survival rates were 64% [95% confidence interval (CI), 44-84%] and 57% (95% CI 35-79%), respectively. CONCLUSION: Pelvic exenteration for recurrent SCC of the cloaca is safe and feasible even after previous salvage surgery. An R0 resection can be achieved in 62.5% of the patients with reasonable early survival though less than published recurrent rectal cancer studies.

Urological leaks after pelvic exenterations comparing formation of colonic and ileal conduits.

BACKGROUND: The aim of this study was to assess possible risk factors for urinary leakage of a newly formed urinary conduit after a partial or total pelvic exenteration. METHODS: An analysis was conducted from prospectively collected data of patients who underwent a pelvic exenteration with conduit formation for advanced and recurrent pelvic cancer. RESULTS: Of 232 patients undergoing a pelvic exenteration, 74 (32%) had a conduit formed. Of these, 47 (64%) had an ileal conduit compared with 27 (36%) a colonic conduit. Twelve (16%) patients developed a leak, of which nine occurred within the first month. Factors associated with a conduit leak included involvement of R2 surgical margins (43%), the magnitude of the exenteration and a current cardiovascular medical history (27%). Leaks were not found to be associated with either radiotherapy or chemotherapy. The 30-day leak rate for ileal conduits was 17% (8/47) and 4% (1/27) for colonic conduits with enterocutaneous fistula only occurring in the ileal conduit group (2/47). Fistula, drained collections and sepsis occurred in 40% of ileal and 19% of colonic conduits (p < 0.01). Patients with a conduit leak had a longer length of stay (59 versus 23 days, p < 0.001). CONCLUSIONS: Urine leaks after conduit formation in association with exenterations are relatively common with a prolonged length of hospital stay. Positive surgical margins and exenterations involving all four quadrants of the pelvis were associated with higher leak rates. There was no evidence of a difference between ileal and colonic conduits and number of leaks. However colonic conduits had less total complications including sepsis, leak and pelvic collections with comparatively no complications of a small bowel fistula.

A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol.

We developed a bronchial provocation test (BPT) with a dry powder preparation of mannitol. The mannitol was inhaled from gelatin capsules containing 5, 10, 20, or 40 mg to a cumulative dose of 635 mg, and was delivered via an inhalator, Halermatic, or Dinkihaler device. We studied the airway sensitivity to inhaled mannitol, the repeatability of the response, and the recovery after challenge in 43 asthmatic subjects 18 to 39 yr of age who had a 20% decrease in FEV1 in response to inhaling a 4.5% NaCl. We compared this with the airway response to methacholine in 25 subjects. The geometric mean (GM) for the dose of dry mannitol required to reduce the FEV1 by 15% of the baseline value (PD15) was 64 mg, with a 95% confidence interval (CI) of 45 to 91. Subjects responsive to mannitol had a PD20 to metacholine of < 7.8 mumol, with a GM of 0.7 mumol (CI: 0.4 to 1.2). For the first of two challenges to mannitol the PD15 was 59 mg (CI: 36 to 97) and for the second the PD15 was 58 mg (CI: 35 to 94) p = 0.91 (n = 23). Spontaneous recovery to within 5% of baseline occurred within 60 min and within 10 min after 0.5 mg terbutaline sulfate was inhaled. Arterial oxygen saturation (SaO2) remained at 93% or above during mannitol challenge. Subjects tolerated the inhalation of the mannitol well. A dry powder preparation of mannitol may be suitable to develop for bronchial provocation testing.

Effect of inhaled frusemide and oral indomethacin on the airway response to hypertonic saline challenge in asthmatic subjects.

BACKGROUND: Inhaled frusemide inhibits airway narrowing and causes a transient increase in forced expiratory volume in one second (FEV1) during hypertonic saline challenge. This inhibitory effect could be secondary to prostaglandin release during challenge. The involvement of prostaglandins in the inhibitory action of frusemide during challenge with 4.5% NaCl was investigated by premedicating with indomethacin, a prostaglandin synthetase inhibitor. METHODS: Fourteen asthmatic subjects (eight women) aged 26.6 (range 18-56) years participated in a double blind, placebo controlled, crossover study. The subjects attended five times and inhaled 4.5% NaCl for 0.5, 0.75, 1, 1.5, 2, 4, 8, 8, and 8 minutes, or part thereof, or until a provocative dose causing a 20% fall in FEV1 (PD20 FEV1) was recorded. Indomethacin (100 mg/day) or placebo were taken three days before all visits, except control day. The FEV1 was measured and frusemide (38.0 (6.4) mg, pH = 9) or vehicle (0.9% NaCl, pH = 9) were inhaled 10 minutes before the challenge. Bronchodilation was calculated as the percentage rise in FEV1 from the prechallenge FEV1 to the highest FEV1 recorded during the challenge. RESULTS: Frusemide caused a fold increase in PD20 FEV1 compared with the vehicle which was similar in the presence of both indomethacin and placebo (3.7 (95% CI 2.0 to 7.3) versus 3.3 (2.0 to 5.4)). Frusemide, but not vehicle, also caused a transient percentage rise in FEV1 during challenge with 4.5% NaCl which was not blocked by indomethacin (3.6% (1.2 to 6.0)) or placebo (3.1% (1.0 to 5.2)). CONCLUSIONS: Inhaled frusemide inhibited airway narrowing and caused a transient increase in FEV1 during challenge with 4.5% NaCl. These effects were not blocked by indomethacin, which suggests that the inhibitory action of frusemide is not secondary to prostaglandin release.

Airway responsiveness in asthma: bronchial challenge with histamine and 4.5% sodium chloride before and after budesonide.

Inhalation of histamine is commonly used to assess the severity of and to monitor treatment of asthma. Histamine causes airways to narrow by acting directly on specific receptors. Hyperosmolar saline causes airways of asthmatics to narrow indirectly by endogenously mediated events that are potentially modified by drugs used to treat asthma. We wished to determine if hyperosmolar saline (S) is a useful challenge for assessing the airway responsiveness of asthmatic subjects being treated with steroids and to compare changes in airway responses to those changes observed with histamine (H). The airway responses to S and H were assessed by the dose of aerosol provoking a 20% fall in FEV1 and the percent fall in FEV1 per unit dose of aerosol inhaled-the dose response slope (DRS). We studied asthmatic subjects before and during treatment with budesonide-1000 micrograms per day. There was a significant correlation (Spearman's) between PD20 to H and S and DRS to H and S after budesonide (P < 0.05). After 2 months of treatment; the mean PD20 (95% CI) was increased 4.6 (2.5, 8.6) fold to H, and 9.7 (4.2, 22) fold to S, (P = NS) the DRS reduced 7.0 (4.3, 11.5) fold to H and 16.6 (8.4, 33) fold to S (P = NS). Responsiveness to H, measured by PD20 remained throughout the treatment, whereas five subjects did not record a 20% fall after S and the DRS decreased to values close to those we measured in healthy subjects. In conclusion, challenge with 4.5% sodium chloride can be used to assess the early benefits of treatment with aerosol steroids.

The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects.

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p<0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.

The protective effect of nedocromil sodium and other drugs on airway narrowing provoked by hyperosmolar stimuli: a role for the airway epithelium?

The airways of persons with asthma are sensitive to acute changes in airway osmolarity and to dehydration. In reviewing the literature it is clear that airway narrowing provoked by these stimuli is blocked acutely by inhaling aerosols of nedocromil sodium, cromolyn sodium, frusemide, bumetanide, and antihistamines and by chronic use of aerosol corticosteroids. The responses are unaffected by inhalation of amiloride and verapamil. We have previously proposed that increases in the osmolarity of airway surface liquid (ASL) occur as a result of the water lost by evaporation during hyperpnea with dry air. An increase or decrease in osmolarity of the ASL will also occur with deposition of hyperosmolar and hypoosmolar droplets. Changes in osmolarity of the ASL result in the movement of water out of (shrinkage) and into (swelling) the epithelial cell, and this necessitates regulatory volume increase or decrease by the cell. We propose that nedocromil sodium and cromolyn sodium can affect water transport into and out of the epithelial cell by an action on chloride ion channels. A unifying hypothesis to explain the protective effect of these drugs may be their capacity to affect regulatory volume increase or decrease in a variety of cell types.

Airway responsiveness to hyperosmolar saline challenge in cystic fibrosis: a pilot study.

Hyperosmolar aerosols are used to assess airway responsiveness in subjects with asthma. Using a 10% NaCl aerosol, we investigated airway responsiveness in 23 cystic fibrosis (CF) subjects (12 females, 11 males; 19.1 +/- 3.3 years) who had asthma-like symptoms. The pre-challenge predicted forced expiratory volume in 1 second (FEV1) was 74.7 +/- 21.5. The aerosol was generated by a MistO2gen 143A ultrasonic nebulizer and inhaled for 0.5, 1, 2, 4, 8, 8, and 8 minutes or part thereof. Spirometry was performed before and 1 minute after each inhalation period. The challenge was stopped when a > or = 20% fall from the baseline FEV1 was recorded, after the last inhalation period, or when requested by the subject. We recorded different responses to 10% NaCl among subjects. In 7, the FEV1 fell progressively throughout the challenge in a manner similar to asthmatics. By contrast, in 15 subjects the FEV1 was higher at the completion of challenge compared to during challenge, i.e., the fall in FEV1 was transient. In 7 of these subjects, the final FEV1 at the end of the challenge was higher than the pre-challenge FEV1. We conclude that inhaled 10% hyperosmolar saline causes either progressive and sustained or transient airway narrowing during challenge in the majority of CF subjects. The cause of the transient airway narrowing requires further investigation.

Acute effect of sodium cromoglycate on airway narrowing induced by 4.5 percent saline aerosol. Outcome before and during treatment with aerosol corticosteroids in patients with asthma.

STUDY OBJECTIVE: To investigate the acute effect of sodium cromoglycate on airway responses to 4.5 percent saline aerosol challenge, before and during treatment with inhaled budesonide--a corticosteroid. DESIGN: Open study, with a total of five visits, two before budesonide treatment, and three follow-up visits, two between 5 and 6 weeks and one at more than 11 weeks. SETTING: Referral-based Respiratory Investigation Unit at Royal Prince Alfred Hospital, a major Sydney-based teaching hospital. PATIENTS: Eleven patients with asthma (ten atopic), with a PD20 FEV1 to 4.5 percent saline aerosol challenge and about to commence inhaled budesonide for treatment of their asthma. INTERVENTIONS: The 40 mg of sodium cromoglycate was inhaled before a 4.5 percent NaCl challenge, both before and after regular (36 +/- 9 d) treatment with budesonide (1,000 micrograms/d). The final challenge was repeated in ten subjects after 11 weeks or more of treatment with budesonide. MEASUREMENTS AND RESULTS: Sensitivity to 4.5 percent saline aerosol was measured as the dose of saline aerosol required to induce a 20 percent fall in FEV1 (PD20). Reactivity was measured as the dose-response slope by taking the percent fall in FEV1 and dividing it by the dose required to induce the fall. On the control day the geometric mean PD20 (95 percent CI) for 4.5 percent saline aerosol was 2.8 (1.4 to 5.4) and the dose response slope (DRS) 5.6 (2.9-11.1). An acute dose of sodium cromoglycate reduced sensitivity (PD20) by 8-fold and reactivity (DRS) 12.3-fold. This effect was similar in magnitude to that measured after regular treatment with budesonide alone. When sodium cromoglycate was given during treatment with budesonide, the PD20 was reduced 16-fold and the DRS 42-fold, and this was greater than the reduction with budesonide taken for 3 months (p < 0.03, p < 0.05 respectively). CONCLUSIONS: Sodium cromoglycate inhibits responses to 4.5 percent saline aerosol and has additional benefits to those conferred by aerosol steroids. The mechanism for responsiveness to saline aerosol and efficacy of these drugs may relate to alteration in chloride ion channel regulation by inflammation.

Different effects of inhaled amiloride and frusemide on airway responsiveness to dry air challenge in asthmatic subjects.

Amiloride, a Na+ channel blocker, and frusemide, an inhibitor of the Na+/K+/2Cl- co-transporter on the basolateral surface of airway epithelial cells, have the potential to affect water transport across the airway epithelium. As isocapnic hyperventilation challenge (ISH) with dry air may provoke airway narrowing in asthmatic subjects by dehydrating the airways, inhaled amiloride and frusemide may reduce airway responsiveness by effecting airway hydration. Fifteen asthmatic subjects (6 females, 9 males), who had a fall in forced expiratory volume in one second (FEV1) of 20% after ISH, inhaled amiloride (11 mg), or its vehicle, from a Fisoneb ultrasonic nebulizer, within 10 min before ISH. On a separate day, eight of these subjects inhaled frusemide (38 mg), from the same Fisoneb, 10 min before ISH. After breathing, 30 l at resting ventilation, subjects breathed at 30% of their maximum voluntary ventilation (MVV i.e. predicted FEV1x35), then at 60% MVV, and finally at MVV for 3 or 4 min. FEV1 was measured 1, 3, 5, 7 and 9 min after each period, or until it was stable. Airway sensitivity was expressed as the ventilation (l-min-1) which provoked a 10, 15, 20 or 30% fall in FEV1, (PVE10, PVE15, PVE20 and PVE30, respectively). There was no significant difference in the PVE10,15,20,30 between the vehicle and amiloride treatment day; however, in the 8 subjects who inhaled frusemide, frusemide caused a significant increase in the PVE20 when compared to amiloride. In conclusion, inhaled amiloride failed to protect against ISH, whereas frusemide was effective at reducing airway responsiveness. Further studies are needed to explain the mechanism of action of frusemide.

The effect of inhaled frusemide on airway sensitivity to inhaled 4.5% sodium chloride aerosol in asthmatic subjects.

BACKGROUND: Frusemide inhaled by asthmatic subjects before a variety of indirect bronchial challenges inhibits the airway response to these challenges. Since inhalation of hyperosmolar saline is an indirect bronchial challenge, the effect of inhaled frusemide and its vehicle on airway sensitivity to a 4.5% sodium chloride (NaCl) aerosol challenge was investigated. METHODS: Eleven asthmatic subjects (five females, six males) who had a 20% fall in forced expiratory volume in one second after 4.5% NaCl challenge were enrolled in this double blind controlled crossover trial. Sensitivity was measured as the dose of aerosol required to provoke a 20% fall in FEV1. Frusemide (33.2 mg) or its vehicle was delivered through a Fisoneb ultrasonic nebuliser and inhaled 10 minutes before challenge with 4.5% NaCl. A Mistogen ultrasonic nebuliser was used to generate the 4.5% NaCl aerosol and FEV1 was measured before and one minute after each challenge period of 0.5, one, two, four, eight, eight and eight minutes. The doubling dose difference for PD20 was calculated. RESULTS: Frusemide or vehicle had no effect on baseline lung function. The geometric mean PD20 after vehicle was 1.3 ml with a 95% confidence interval of 0.7-2.3 and after frusemide was 8.2 ml with a 95% confidence interval of 4.7-14.1. This represented a 2.6 doubling dose increase in PD20 after frusemide inhalation. In five of the 11 subjects an increase from baseline FEV1 occurred after exposure to 4.5% NaCl challenge in the presence of frusemide. This transient bronchodilatation may be caused by the release of prostaglandin E2. CONCLUSION: Inhalation of frusemide is very effective in delaying airway narrowing induced by an aerosol of 4.5% NaCl in asthmatic subjects.

Nedocromil sodium inhibits the airway response to hyperosmolar challenge in patients with asthma.

We studied 16 asthmatic subjects sensitive to changes in airway osmolarity to determine whether nedocromil sodium has any effect on airway narrowing caused by hypertonic saline challenges. Nedocromil sodium (10 mg) or its vehicle was inhaled 10 min before a challenge with ultrasonically nebulized 4.5% NaCl. FEV1 was measured before challenge and 1 min after each challenge period of 0.5, 1, 2, 4, 8, 8 and 8 min. The challenge was stopped when there was a 20% fall in FEV1 from baseline or after the final challenge period. We measured airway sensitivity, that is, the provoking dose of 4.5% NaCl required to induce a 20% reduction in FEV1 (PD20FEV1) and calculated the fold difference in PD20FEV1 after the intervention. After inhaling nedocromil sodium there was a 3.95-fold improvement in PD20 (p < 0.001) when compared with the vehicle day. After pretreatment with nedocromil sodium two of the 16 subjects were completely protected against 4.5% NaCl challenge, and six developed a plateau in their response. We conclude that nedocromil sodium is effective in reducing airway narrowing in response to 4.5% NaCl challenge in asthmatic subjects, and it appears to be unique in its ability to produce a plateau in response to acute administration of a drug before a bronchial challenge.

Inhaled steroids modify bronchial responses to hyperosmolar saline.

We investigated the effects of inhaled beclomethasone dipropionate (BDP) on airway sensitivity (provocative dose producing a 20% fall in forced expiratory volume in one second (FEV1) from baseline (PD20)) and reactivity (slope of the dose-response curve) to inhaled aerosols of hyperosmolar (4.5%) saline, and histamine or methacholine. This was an open study on 13 patients referred to the laboratory by their respiratory physician for investigation of their asthma. These challenges were performed on separate days before (initial visit) and 8.8 +/- 0.8 (SD) weeks (range 5.6-12.4 weeks) after (visit 1) a treatment period with BDP (dose range 600-1,500 micrograms.day-1). At visit 1 there was a significant reduction in sensitivity to 4.5% NaCl and histamine/methacholine and in reactivity. The PD20 increased 5.6 fold for 4.5% NaCl and 4.1 fold for histamine/methacholine. All patients remained responsive to histamine/methacholine and a fall in FEV1 > 20% to 4.5% saline was documented in 10 of the 13 patients. We conclude that treatment with BDP reduces sensitivity and reactivity to both osmotic and pharmacological challenge.

Duration of protection by inhaled salmeterol in exercise-induced asthma.

Beta-adrenoceptor agonists such as albuterol are very effective in preventing exercise-induced asthma (EIA) when they are given as an aerosol immediately before exercise. However, their duration of protection against EIA is usually less than 2 h. This may be due partly to their rapid clearance from the airways. Salmeterol is a highly lipophylic compound that is thought to bind to an exoreceptor near the beta-receptor. The objective of this study was to compare the protective effect of salmeterol with albuterol against EIA. Exercise was performed 0.5, 2.5, 4.5, and 6.5 hours after administration of the active drugs. Subjects attended the laboratory on four days within six weeks and cycled for 8 min breathing dry compressed air. We studied 17 asthmatic subjects (aged 19 to 49 years) with moderate to severe EIA. Salmeterol (50 micrograms) or albuterol (200 micrograms) was given from a metered dose inhaler via a spacer (Volumatic). On the control day, the mean work load +/- 1 SD was 174 +/- 47 W, ventilation (VE) was 77.9 percent +/- 11.2 percent of the target ventilation (60 percent maximum voluntary ventilation [MVV]), and heart rate was 170 +/- 14 beats per minute. This intensity was maintained for all tests. FEV1 was measured before and after exercise and was expressed as percent predicted and as percentage of the preexercise value (percentage of fall). Thirty minutes after treatment, both drugs were effective in inhibiting EIA--percentage of fall in FEV1, 17 +/- 12 after salmeterol; percentage of fall in FEV1, 15 +/- 15 after albuterol. At 2.5, 4.5, and 6.5 hours, the reduction in FEV1 was significantly less (p less than 0.01) after salmeterol compared with albuterol. At 6.5 hours, the percentage of fall in FEV1 was 20 +/- 10 after salmeterol and 36 +/- 12 after albuterol. Salmeterol also had a more prolonged action as a bronchodilator and values for FEV1 were significantly higher compared with those on albuterol at 4.5 and 6.5 hours. At 6.5 hours, the FEV1 percent predicted was 96 +/- 10 after salmeterol and 84 +/- 12 after albuterol (p less than 0.01). We conclude that the extent of protection against EIA and the bronchodilation induced by both drugs was similar, but that salmeterol has a longer duration of action compared with albuterol. The reason for its superior duration of action may be due to a slower clearance of the drug from the airways.

Inhaled clemastine, an H1 antihistamine inhibits airway narrowing caused by aerosols of non-isotonic saline.

Asthmatic subjects were challenged with aerosols of hyper- and hypotonic saline 15 min (Group A) and 90 min (Group B) after inhaling clemastine. Measurements were made of forced expiratory volume in one second (FEV1) before and after medication and after challenge. When the FEV1 values (% predicted) were compared on the active and placebo days they were higher 15 min after clemastine (p less than 0.05) for both challenges and higher 90 min after clemastine inhalation (p less than 0.05) for the hypertonic challenge. The % fall in FEV1 was compared after the same concentration of saline aerosol had been given on both active and placebo days. In Group A the % fall in FEV1 on the clemastine day was reduced after challenge with hypertonic (p less than 0.02) and hypotonic (p less than 0.03) aerosol. In Group B there was a reduction in the % fall in FEV1 on the clemastine day only after hypertonic challenge (p less than 0.04). The protective effect afforded by clemastine was unrelated to change in baseline lung function. We conclude that histamine is an important mediator of the airway response to non-isotonic aerosols and suggest that the aerosol route of administration may be useful for delivering antihistamines.