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Background: Naxitamab is a humanized GD2-binding monoclonal antibody that received accelerated approval from the U.S. Food and Drug Administration for refractory or relapsed high-risk neuroblastoma limited to bone or bone marrow. Trial 201 (NCT03363373) is an ongoing global clinical trial to evaluate the efficacy and safety of naxitamab in combination with granulocyte-macrophage colony-stimulating factor in this population., Aims: Here, we review the safety profile and adverse event (AE) management associated with naxitamab administration in a pediatric population, based on Trial 201 protocol guidelines and clinical trial experience., Methods and Results: At least 50% of patients experienced pain, hypotension, bronchospasm, cough, vomiting, diarrhea, nausea, and tachycardia, with the following reported at grade ≥3 AEs for at least 10% of patients: pain, hypotension, urticaria, and bronchospasm. These AEs were generally manageable in the outpatient setting using premedications, supportive therapies, and appropriate monitoring post-infusion. Algorithms were established for infusion-related AEs, including hypotension and bronchospasm, to provide guidance to investigators for early recognition and timely intervention, including medication and infusion rate modification or interruption, or treatment discontinuation, based on AE severity. Educating patients and caregivers on what to expect regarding premedication at home, experience during the infusion cycle, and post-infusion monitoring helps optimize naxitamab treatment and supportive therapies and may reduce treatment burden., Conclusion: This article highlights the protocol-based recommendations for the management of acute AEs associated with outpatient naxitamab treatment in Trial 201. The authors recommend close monitoring and timely implementation of measures to ensure that patients can remain on treatment and obtain maximum clinical benefit from naxitamab therapy., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Ketamine is used in intravenous anesthesia for the maintenance in the general anesthesia. It has characteristics to prevent the difficult of breathing due to bronchospasm, as well as the delivery of histamine associated with asthmatic attack. These effects come from the direct action in the bronchial muscle, as well as from the potentiation of its catecholamines, which is why its use is very controversial, given that there are not enough trials to back it up. Moreover, the effect of ketamine on bronchospasm due to anaphylactic reaction has not been studied. The election treatment is epinephrine and there are factors associated with its use. The objective was to present the case of a patient with a history of allergic reaction to midazolam, who presented bronchospasm due to the administration of this drug, and who received unconventional treatment with positive outcomes., Clinical Case: We present the case of a young female with a history of allergies to medicines, specifically to benzodiazepines, who presented bronchospasm and oxygen saturation drop after receiving a dose of midazolam into her eye while she was working. The use of ketamine was proposed after adrenaline, a beta-agonist, inhaled anticholinergics, a steroid and antihistamine drugs were used., Conclusion: Trials are needed in order to demonstrate the efficacy of ketamine in this particular context; however, the outcome in this case was positive., (© 2022 Revista Medica del Instituto Mexicano del Seguro Social.)

Background: Sugammadex and neostigmine given to reverse residual neuromuscular blockade can cause side effects including bradycardia, anaphylaxis, bronchospasm, and even cardiac arrest. We tested the hypothesis that sugammadex is noninferior to neostigmine on a composite of clinically meaningful side effects, or vice versa., Methods: We analyzed medical records of patients who had general, cardiothoracic, or pediatric surgery and were given neostigmine or sugammadex from June 2016 to December 2019. Our primary outcome was a collapsed composite of bradycardia, anaphylaxis, bronchospasm, and cardiac arrest occurring between administration of the reversal agent and departure from the operation room. We a priori restricted our analysis to side effects requiring pharmacologic treatment that were therefore presumably clinically meaningful. Sugammadex would be considered noninferior to neostigmine (or vice versa) if the odds ratio for composite of side effects did not exceed 1.2., Results: Among 89,753 surgeries in 70,690 patients, 16,480 (18%) were given sugammadex and 73,273 (82%) were given neostigmine. The incidence of composite outcome was 3.4% in patients given sugammadex and 3.0% in patients given neostigmine. The most common individual side effect was bradycardia (2.4% in the sugammadex group versus 2.2% neostigmine). Noninferiority was not found, with an estimated odds ratio of 1.21 (sugammadex versus neostigmine; 95% confidence interval [CI], 1.09-1.34; noninferiority P = .57), and neostigmine was superior to sugammadex with an estimated odds ratio of 0.83 (0.74-0.92), 1-side superiority P < .001., Conclusions: The composite incidence was less with neostigmine than with sugammadex, but only by 0.4% (a negligible clinical effect). Since 250 patients would need to be given neostigmine rather than sugammadex to avoid 1 episode of a minor complication such as bradycardia or bronchospasm, we conclude that sugammadex and neostigmine are comparably safe., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Background: Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days., Methods: This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis., Results: A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups., Conclusions: In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Rationale: Cis-atracurium as an intermediate-acting non-depolarizing neuromuscular blocker is widely used clinically with less causing cyclic fluctuations and less histamine release. As the use rate increases, allergic reactions and anaphylactoid reactions caused by cis-atracurium increase., Patient Concerns: A 23-year-old woman underwent laparoscopic bariatric surgery. Airway spasm occurred after anesthesia induction and the operation was suspended. After adjustment, the anesthesia was performed with the same anesthetic scheme again. After induction, skin flushing and airway resistance increased, then the symptoms were relieved. When the cis-atracurium was given again, the symptoms of airway spasm reappeared immediately, and after communicating with the family, the operation was successfully completed with rocuronium., Diagnoses: Serious bronchospasm induced by cisatracurium besylate., Interventions: The patient was undergone assisted ventilation with continuous positive airway pressure (CPAP) and aminophylline 250 mg, methylprednisolone 80 mg were given intravenously., Outcomes: There was no any obvious discomfort in the patient's self-report during the next day's visit. The patient was discharged 7 days later. No abnormalities were observed during following 4 weeks., Lessons: Although the anaphylactoid reactions caused by cis-atracurium are rare, the bronchospasm and anaphylactic shock caused by it greatly increase the risk of anesthesia, which should be taken seriously by clinicians. Increased vigilance in diagnosis, and treatment are essential to prevent aggravation and further complication., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Although postoperative early airway complications are rarely observed, when they do develop, fatal results such as brain damage and cardiac arrest may occur. The Royal College of Anaesthetists and Difficult Airway Society investigated airway complications developing during anaesthesia over a period of 12 months within the context of the Fourth National Audit Project (NAP4) study. Inspired by that multicentre research project, this study aims to identify early airway complications that can develop in relation to anaesthesia induction in our hospital., Methods: After our proposed study received approval from the Ethical Council, adult patients undergoing general anaesthesia at our operating theatres within the period of January-July 2018 were included in it. Demographic data, ventilation, American Society of Anesthesiologists (ASA) grade, Cormack-Lehane scores, tools that are used in airway management, and complications were recorded., Results: Out of 909 patients in total, 752 were intubated; a laryngeal mask was placed on 157 of these patients. The complication rate was 5%, and the 3 most frequently observed complications were desaturation, bronchospasm and pharyngeal injuries. In the group having complications, the body mass index value, Cormack-Lehane, Mallampati, and ventilation scores were significantly higher than those with no complications., Conclusions: During routine general anaesthesia induction at our clinic, major or minor airway complications have developed with a frequency of 5%, and it was determined that desaturation was the most frequent reversible cause.

Background: Adenosine is frequently used during coronary angiography to induce hyperaemia and allow operators to perform quantitative measurements of lesion severity. Acute bronchospasm is a recognised side effect relating to the activation of 'off target' A2B receptors. The true incidence of severe bronchospasm relating to adenosine administration is not known., Methods: Using an electronic patient database, we analysed 100,253 consecutive coronary angiograms over almost 19 years. Fractional flow reserve (FFR) was measured under systemic adenosine in 9,440 cases., Results: Adenosine-related bronchospasm was reported in only five cases (0.05%). One case resulted in a life-threatening respiratory arrest., Conclusions: This study reveals the incidence of acute bronchospasm during FFR testing to be extremely low. Although rare, these reactions can be severe and are not simply limited to patients with brittle airways disease. Physicians should be aware of the utility of bolus intravenous aminophylline providing targeted therapy to reverse and treat adenosine-related bronchospasm., Competing Interests: No conflict of interests declared

Bronchospasm represents the clinical manifestation of bronchial muscles contraction resulting in reduced alveolar air flow. Non-allergic mechanisms or anaphylaxis underlie the genesis of perioperative bronchospasm, a potential anaesthetic disaster. Early recognition and treatment are crucial. We report a rare incident of anaphylactic bronchospasm without hypotension during general anaesthesia. Urticaria appeared in chest and abdomen suggesting anaphylaxis. After the event resolved with bronchodilators, surgery continued uneventfully. Vecuronium was the most probable culprit but confirmation was not possible as the patient was lost to follow up. Rarely, perioperative anaphylaxis presents only with bronchospasm that requires prompt attention to avoid adverse outcome. Keywords: allergy; anaphylaxis; bronchial spasm; general anesthesia.

Cocaine can cause a myriad of changes in the lung, which can range from bronchoconstriction to destruction of the alveolar-capillary membrane and acute lung injury. Cocaine-induced bronchospasm is a diagnosis of exclusion that should be considered when the clinical presentation of acute hypoxic and hypercapneic respiratory failure cannot be explained by chronic obstructive pulmonary disease or asthma exacerbation, anaphylaxis to food or medications, exercise, or infection. Here, we present two patients with acute hypoxic and hypercapneic respiratory failure that was ultimately attributed to cocaine use shortly prior to symptom onset., (© 2019 Marshfield Clinic.)

Objective: To describe the clinical-epidemiological characteristics of a series of suspected systemic adverse reactions registered with the 23 serotype pneumococcal polysaccharide vaccine (PNEUMOVAX23®). Calculate the cumulative incidence of the reaction and know if similar and/or compatible cases have been described in the scientific literature or in pharmacovigilance., Methods: Observational and retrospective study realized between 01/12/2015 and 30/09/2017 in the Vaccines Unit of an autonomic reference hospital. We calculated the cumulative incidence of the adverse reaction for that vaccine. The common pharmacovigilance database (FEDRA) was consulted., Results: Nine systemic adverse reactions were recorded (flushing + bronchospasm + SatO2<95%). The cumulative incidence was 1.036%. The outcome was recovered/resolved for everyone. No similar and/or compatible cases were found., Conclusions: The reactions described do not appear in the PNEUMOVAX23® data sheet. Epidemiologically, no causal relationship can be established between the symptoms and the variables studied. This study could be the basis for more detailed research that could modify the vaccine data sheet., (©The Author 2019. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Background: The aim of this study was to compare the effect of propofol and ketofol (ketamine-propofol mixture) on EA in children undergoing tonsillectomy., Method: In this randomized clinical trial, 87 ASA class I and II patients, aged 3-12 years, who underwent tonsillectomy, were divided into two groups to receive either propofol 100 µg/kg/min (group p, n=44) or ketofol : ketamine 25 µg/kg/min + propofol 75 µg/kg/min (group k, n= 43). Incidence and severity of EA was evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scales on arrival at the recovery room, and 10 and 30 min after that time., Results: There was no statistically significant difference in demographic data between the two groups. In the ketofol group, the need for agitation treatment and also mean recovery duration were lower than in the propofol group (30 and 41%, and 29.9 and 32.7 min), without statistically significant difference (P value=0.143 and P value=0.187). Laryngospasm or bronchospasm occurred in 2 patients in each group and bleeding was observed in only one individual in the ketofol group., Conclusion: Infusion of ketofol in children undergoing tonsillectomy provides shorter recovery time and lower incidence of EA despite the non significant difference with propofol.

Background: Inhaled interferon, a potential treatment for idiopathic pulmonary fibrosis, must be formulated with mannitol, which can cause bronchospasm and cough. Coughing during drug inhalation can be affected by many factors, but some factors are fixed by the needs of the formulation and inflammatory disease in the airways. A component of the cough response may be related to sites of deposition, particularly upper and central airways. If deposition sites are important, then manipulating the particle distribution of the aerosol may mitigate coughing. To design a therapeutic formulation and delivery system for formulations that contain mannitol, we tested the effect of particle distribution on cough during mannitol inhalation in volunteers with idiopathic pulmonary fibrosis., Methods: A solution of mannitol was formulated to match requirements for future interferon formulations (40 mg/mL, 220 mOsm/L). Mannitol aerosols were generated by using different nebulizers providing particle distributions that were expected to vary upper airway deposition. The nebulizer fill volume was adjusted to correct for differences in nebulizer efficiency with a target inhaled mass of 20 mg. Particle distributions were measured by cascade impaction (mass median aerodynamic diameters, 1.2 and 6.5 μm). Seven subjects with idiopathic pulmonary fibrosis participated in the study. To maximize deposition, the subjects were trained to inhale slowly and deeply (6 s inspiration). Spirometry was measured before and after inhalation. The study was carried out on separate days (day 1: 1.2 μm; day 2: 6.5 μm), and the pattern of coughing was observed., Results: Coughing was often spontaneous and provoked by spirometry. When inhaling the 1.2-μm distribution, no subject coughed during inhalation. Six of the seven subjects coughed when inhaling the 6.5-μm particles. Spirometry was unaffected., Conclusions: In subjects with idiopathic pulmonary fibrosis, nebulized mannitol can cause coughing. Modifying the aerosol distribution prevents coughing during mannitol inhalation. Mannitol aerosols can be inhaled safely without bronchospasm. These data serve to inform future formulation and/or device combinations for planned interferon therapy., (Copyright © 2018 by Daedalus Enterprises.)

Background: In early 2015, clinicians throughout Zambia noted a range of unpredictable adverse events after the administration of propofol, including urticaria, bronchospasm, profound hypotension, and most predictably an inadequate depth of anesthesia. Suspecting that the propofol itself may have been substandard, samples were procured and sent for testing., Methods: Three vials from 2 different batches were analyzed using gas chromatography-mass spectrometry methods at the John L. Holmes Mass Spectrometry Facility., Results: Laboratory gas chromatography-mass spectrometry analysis determined that, although all vials contained propofol, its concentration differed between samples and in all cases was well below the stated quantity. Two vials from 1 batch contained only 44% ± 11% and 54% ± 12% of the stated quantity, whereas the third vial from a second batch contained only 57% ± 9%. The analysis found that there were no hexane-soluble impurities in the samples., Conclusions: None of the analyzed vials contained the stated amount of propofol; however, our analysis did not detect additional contaminants that would explain the adverse events reported by clinicians. Our results confirm the presence of substandard propofol in Zambia; however, anecdotal accounts of substandard anesthetic medicines in other countries abound and warrant further investigation to provide estimates of the prevalence and scope of this global problem.

Angiotensin converting enzyme (ACE) inhibitors therapy is aassociated with bothersome dry cough as an adverse effect. The mechanisms underlying this adverse effect are not clear. Therefore, influence of captopril (an ACE inhibitor) on acetylcholine (ACh)-induced bronchial smooth muscle contractions was investigated. Further, the mechanisms underlying the captopril-induced changes were also explored. In vitro contractions of rat bronchial smooth muscle to cumulative concentrations of ACh were recorded before and after exposure to captopril. Further, the involvement of kinin and inositol triphosphate (IP₃) pathways for captopril-induced alterations were explored. ACh produced concentration-dependent (5-500 µM) increase in bronchial smooth muscle contractions. Pre-treatment with captopril augmented the ACh-induced contractions at each concentration significantly. Pre-treatment with aprotinin (kinin synthesis inhibitor) or heparin (inositol triphosphate, IP₃-inhibitor), blocked the captopril-induced augmentation of bronchial smooth muscle contractions evoked by ACh. Further, captopril-induced augmentation was absent in calcium-free medium. These results suggest that captopril sensitizes bronchial smooth muscles to ACh-induced contractions. This sensitization may be responsible for dry cough associated with captopril therapy.

Outbreaks ofPneumocystispneumonia have been described in renal transplant recipients. Aerosolized pentamidine is frequently used for prophylaxis in this setting. We report our experience with aerosolized pentamidine use in 56 renal transplant recipients. We found high rates of adverse reactions in patients with chronic respiratory disease., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: AZD9164 has demonstrated potential as an inhaled, long-acting, muscarinic antagonist (LAMA) bronchodilator. However, in patients with COPD, but not in healthy subjects, a transient initial drop in FEV1 was observed following inhalation of nebulised doses of AZD9164 in citrate buffer.Two additional studies were conducted to further assess the safety and tolerability of multiple ascending doses of AZD9164 in 27 white and 18 Japanese healthy subjects and in 4 patients with COPD. In these studies, AZD9164 was inhaled via Turbuhaler™., Methods: These were Phase I, randomised, double-blind, placebo-controlled, multiple ascending dose (MAD) studies conducted in Sweden and UK. Healthy subjects (mean age 25.9 yrs) and patients with COPD (mean age 66 yrs, mean post-bronchodilator FEV1 60.1% predicted normal value) were randomised 2:1 to active treatment (400, 1000 or 2800 μg delivered doses of AZD9164) or placebo., Results: No safety or tolerability concerns were identified in the healthy subjects at doses up to and including 2800 μg and both studies confirmed the bronchodilator effect of AZD9164. However, the first 3 patients in the COPD cohort who received AZD9164 (1000 μg) experienced a transient fall in FEV1 5 to 15 minutes after inhalation of AZD9164 while the patient receiving placebo did not. The study safety review process then resulted in cessation of further activities on AZD9164. Retrospective analysis showed that two healthy subjects had also had transient falls in FEV1 shortly after inhalation of AZD9164 400 and 2800 μg respectively, although neither reported any related respiratory symptoms or other AEs., Conclusions: These results show that transient paradoxical bronchoconstriction can occur in some healthy subjects, in addition to patients with COPD, following inhalation of AZD9164 and that the citrate buffer used in the nebulised formulation cannot have been the only cause of the drop in FEV1 in previous studies. As preclinical data do not provide an explanation, the reasons for this brief post-dose drop in FEV1 remain unclear. However, these results highlight the importance of monitoring lung function immediately post-dose when investigating novel inhaled treatments, even when a rapid onset of effect is not expected., Trial Registration: Clinicaltrials.gov NCT01016951 and NCT01096563.

Activation of vagal afferent sensory C-fibres in the lungs leads to reflex responses that produce many of the symptoms associated with airway allergy. There are two subtypes of respiratory C-fibres whose cell bodies reside within two distinct ganglia, the nodose and jugular, and whose properties allow for differing responses to stimuli. We here used extracellular recording of action potentials in an ex vivo isolated, perfused lung-nerve preparation to study the electrical activity of nodose C-fibres in response to bronchoconstriction. We found that treatment with both histamine and methacholine caused strong increases in tracheal perfusion pressure that were accompanied by action potential discharge in nodose, but not in jugular C-fibres. Both the increase in tracheal perfusion pressure and action potential discharge in response to histamine were significantly reduced by functionally antagonizing the smooth muscle contraction with isoproterenol, or by blocking myosin light chain kinase with ML-7. We further found that pretreatment with AF-353 or 2',3'-O-(2,4,6-Trinitrophenyl)-adenosine-5'-triphosphate (TNP-ATP), structurally distinct P2X3 and P2X2/3 purinoceptor antagonists, blocked the bronchoconstriction-induced nodose C-fibre discharge. Likewise, treatment with the ATPase apyrase, in the presence of the adenosine A1 and A2 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and SCH 58261, blocked the C-fibre response to histamine, without inhibiting the bronchoconstriction. These results suggest that ATP released within the tissues in response to bronchoconstriction plays a pivotal role in the mechanical activation of nodose C-fibres.

The therapeutic arsenal for hemangiomas in early childhood can now be considered to include oral β-blockers, mainly propranolol. These drugs are thought to act as vasoconstrictors, regulating angiogenic pathways and inducing apoptosis of vascular endothelial cells. Although infantile hemangioma is not among the approved indications for β-blockers, many specialized clinics will prescribe propranolol before resorting to corticosteroids. A dosage of 2 mg/kg/d, is usually employed with a dosing interval of 8 hours. Propranolol is safe, causing few side effects, although cases of hypoglycemia, hypotension, diarrhea, reflux, cold hands and feet, bronchospasm, and hyperkalemia have been described. Generally, these adverse effects have not had serious consequences. Prescription in PHACE syndrome is controversial. In all cases, a cardiologist should assess the patient before treatment begins, blood pressure should be monitored, and pediatric follow-up should be scheduled. This review covers our current understanding of the indications, clinical response, and adverse effects of propranolol, a drug has revolutionized our attitude toward infantile hemangioma and the way we approach therapy. Clinical trials under way are also reviewed., (Copyright © 2011 Elsevier España, S.L. y AEDV. All rights reserved.)

Objective: To discuss phytopharmacological potential and anti-asthmatic activity of Ficus religiosa (F. religiosa) (L.)., Methods: Fresh leaves of F. religiosa were obtained from Vastrapur Lake, Ahmedabad, and dried to obtain powder. Histamine and acetylcholine were used to guinea pigs to establish bronchospasm model. In in vivo study, the aqueous extract of F. religiosa leaves (AEFR) at doses of 150 and 300 mg/kg was administrated to guinea pigs, and the broncho-protective activity of AEFR was compared with aminophylline at 25 mg/kg. While in in vitro study, and 10 g/mL, 20 g/mL, 30 g/mL of AEFRL was administrated to guinea pigs, respectively, and mast cell stabilizing activity of AEFR was compared with ketotifen at 10 g/mL., Results: In the in-vivo model, pre-treatment with aminophylline (25 mg/kg, ip.) could significantly delay the onset of histamine induced pre-convulsive dyspnea, compared with vehicle control. Administration of AEFRL (150 and 300 mg/kg, ip.) also produced significant effect on latency to develop histamine & acetylcholine induced pre-convulsive dyspnea. In the mast cell stabilizing model, AEFRL at 10, 20 and 30 μg/mL could significantly increase the number of intact cells., Conclusions: It can be concluded that AEFRL is effective on histamine & acetylcholine induced bronchospasm in guinea pigs. In addition, AEFRL can potentiate the number of intact cells in the mast cell stabilizing model., (Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.)

Background: Cystic fibrosis (CF) is characterised by impaired mucociliary clearance (MCC), chronic inflammation and infection, and progressively deteriorating lung function. Inhaled mannitol (Bronchitol) has been shown to increase MCC and cough clearance and FEV(1) in CF patients, contributing to better lung hygiene and consequently a slower decline in lung function. This study was designed to determine the dose relationship of mannitol treatment and improvement in FEV(1) and FVC as well as safety., Methods: This was a randomised, open-label, crossover, dose response study. Following a 2-week treatment with mannitol 400mg b.i.d., 48 CF patients with a mean (SD) FEV(1) % predicted of 64 (13.2), received a further 3 treatments with 40mg, 120mg or 240mg b.i.d. for 2weeks each, in random order., Results: The study demonstrated a dose dependent increase in FEV(1) and FVC. The 400mg dose showed the greatest improvement and the 40mg dose had no discernible effect. The mean percent change in FEV(1) was -1.57%, 3.61%, 3.87% and 8.75% respectively for the 40mg, 120mg, 240mg and 400mg treatments. There was a statistically significant change in FEV(1) for 400mg compared to 40mg (p<0.0001) but the difference with 120mg and 240mg did not reach significance. The mean % change in FVC was -0.90, 1.74, 3.07 and 8.14, for the 40mg, 120mg, 240mg and 400mg treatment arms, with p=0.0001, p=0.0037 and p=0.0304 respectively when compared to 400mg. The highest tested dose of 400mg had a similar safety profile to the other doses tested. The change in FEV(1) and FVC by dose in the paediatric age group (<18years) was similar to the results in the adult population., Conclusion: Based on these results the 400mg b.i.d. dose has been further studied in phase III trials., (Copyright © 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat(®) Soft Mist™ Inhaler (SMI). We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks' treatment with once-daily tiotropium (5 or 10 μg) or placebo inhaled via Respimat(®) SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3%) reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1%) reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in forced expiratory volume in one second (FEV(1)) of ≥15% were recorded on all test days, with no change in incidence over time, and affected 8.2% of those in the tiotropium groups and 14.5% of those on placebo. In COPD patients receiving long-term treatment with tiotropium 5 or 10 μg via Respimat(®) SMI, no bronchospasm was recorded, and the number of events possibly indicative of paradoxical bronchoconstriction was very low.

Background: Anaphylactic reaction induced bronchospasm as wheezing and severe elevation of airway pressure was observed in a succession of patients during general anesthesia at our institute in November 2007. The aim of this survey was to investigate the suspected causes and risk factors of these anaphylactic reactions and the degree of correlation., Methods: All patients who received general anesthesia between November 1 and November 10, 2007 were enrolled. Underlying diseases, substances including intravenous and inhalational anesthetics, antibiotics, and the degree of increase in airway pressure were recorded. Enrolled patients were divided into a significant-airway-pressure-elevation group (Group P) and a no-airway-pressure-elevation group (Group N)., Results: A new brand of cephalexin (Roles) used as a prophylactic antibiotic was identified as the most likely causative substance of this succession of suspected anaphylactic reactions (28 in 185 patients, 15.14%), and rapid administration was a contributor to these anaphylactic reactions., Conclusion: In this study, we found that rapid administration of Roles was the main cause of suspected anaphylactic reaction presenting as bronchospasm with severe elevated airway pressure. Using Roles as the prophylactic antibiotic is not recommended in patients receiving general anesthesia., (Copyright 2010 Elsevier. Published by Elsevier B.V. All rights reserved.)

Background: Tobacco smoke is a key risk factor for chronic obstructive pulmonary disease, but it may also alter the pathophysiology of asthma. In the present study, we analyzed whether tobacco smoke has acute or chronic effects on bronchial tone and whether it alters bronchial reactivity in vitro., Methods: Airways in murine lung slices were digitally recorded and the change in cross-sectional area with time was quantified. T-bet KO mice served as a model for bronchial hyperreactivity. T-bet KO mice show a shift towards type 2 helper T lymphocytes and display histological as well as functional characteristics of asthma. Cigarette smoke extract (CSE) was obtained using commercially available cigarettes (Gauloise Blondes) by drawing cigarette smoke slowly through a water pump into a tube containing 10 mL of DMEM culture medium., Results: Acute exposure to CSE led to relaxation of the airway. Acute exposure to nicotine resulted in a minor relaxation of the airway in Balb/C mice and in nonsignificant relaxation of the airway in T-bet KO mice. The nicotinic acetylcholine-receptor hexamethonium partially inhibited CSE-induced airway relaxation. Airway contraction in response to acetylcholine was stronger in T-bet KO mice than in Balb/C mice. After exposure to CSE or nicotine for 48 hours, acetylcholine-induced airway contraction was no longer different between the 2 types of mice., Conclusions: Our data indicate that acute exposure to CSE leads to airway relaxation, which is partially mediated by nicotine. Chronic exposure to CSE reverses bronchial hyperreactivity in the airways of T-bet KO mice; this effect can be mimicked by chronic exposure to nicotine.

Background: Beta-Blockers are often withheld from patients with obstructive airways disease, especially those with reversible airways disease due to fear of inducing bronchospasm. We report our single center experience of cautiously treating such patients who have concomitant chronic heart failure (CHF)., Hypothesis: The use of cardioselective beta-blockers under caution and specialist supervision may be tolerable in many CHF patients with obstructive airways disease, resulting in clinical improvement rather than detriment., Methods: A retrospective case notes analysis was performed on CHF outpatients who had obstructive airways disease and been treated with beta-blockers., Results: A total of 43 patients were identified, with an average ejection fraction of 31.8%; 18 of these patients had fixed obstructive airways disease, 15 patients had reversible obstructive airways disease, 10 patients had a label of obstructive airways disease (but no supporting evidence for the diagnosis in the hospital notes). In all 3 groups, beta-blockers had been initiated and maintained without any respiratory event over a median continuous exposure time of 135 days. Limitation of the dose was documented in only 2 patients because of worsening shortness of breath. New York Heart Association (NYHA) class significantly improved for the group with the use of these agents (p = 0.003)., Conclusion: A cautious approach (under specialist supervision) to beta-blocker use in patients with heart failure and airways disease can result in successful treatment. The implications of withholding these agents may have more serious consequences than their administration.

Objective: Evaluate whether exhaled nitric oxide may serve as a marker of intraoperative bronchospasm., Introduction: Intraoperative bronchospasm remains a challenging event during anesthesia. Previous studies in asthmatic patients suggest that exhaled nitric oxide may represent a noninvasive measure of airway inflammation., Methods: A total of 146,358 anesthesia information forms, which were received during the period from 1999 to 2004, were reviewed. Bronchospasm was registered on 863 forms. From those, three groups were identified: 9 non-asthmatic patients (Bronchospasm group), 12 asthmatics (Asthma group) and 10 subjects with no previous airway disease or symptoms (Control group). All subjects were submitted to exhaled nitric oxide measurements (parts/billion), spirometry and the induced sputum test. The data was compared by ANOVA followed by the Tukey test and Kruskal-Wallis followed by Dunn's test., Results: The normal lung function test results for the Bronchospasm group were different from those of the asthma group (p <0.05). The median percentage of eosinophils in induced sputum was higher for the Asthma [2.46 (0.45-6.83)] compared with either the Bronchospasm [0.55 (0-1.26)] or the Control group [0.0 (0)] (p <0.05); exhaled nitric oxide followed a similar pattern for the Asthma [81.55 (57.6-86.85)], Bronchospasm [46.2 (42.0 -62.6] and Control group [18.7 (16.0-24.7)] (p< 0.05)., Conclusions: Non-asthmatic patients with intraoperative bronchospasm detected during anesthesia and endotracheal intubation showed increased expired nitric oxide.

Background: Beta-blockers are frequently withheld in patients with cardiovascular disease who also have chronic obstructive pulmonary disease (COPD) because of concerns that they might provoke bronchospasm and cause deterioration in health status. Although beta1-selective beta-blockers are associated with reduced mortality in COPD patients, their effects on health status are unknown. The aim of this study was to investigate the relationship between beta-blockers and health-related quality of life (HRQOL) in patients with peripheral arterial disease and COPD., Methods: Of the original cohort of 3371 vascular surgery patients, 1310 had COPD of whom 469 survived during long-term follow-up. These COPD patients were sent the Short Form-36 (SF-36) health-related quality of life questionnaire, which was completed and returned by 326 (70%) patients., Results: No significant differences in any of the SF-36 domains were observed between COPD patients who did and did not use beta-blockers (p > 0.05 for all). Furthermore, beta-blockers were not associated with any impairment in HRQOL among patients with COPD., Conclusion: Beta-blockers had no material impact on the HRQOL of patients with peripheral arterial disease who also had COPD. This suggests that beta-blockers can, in most circumstances, be administered to patients with COPD without impairment in HRQOL.

IV lidocaine (1.5 mg/kg) administered to facilitate endotracheal intubation was associated with transient bronchospasm in a 17-month-old-female with mild intermittent asthma. Immediately after lidocaine administration, the patient developed diffuse bilateral expiratory wheezes and dramatic increases in peak inspiratory pressure. Over approximately 5 min the episode resolved and an uneventful anesthetic course followed. This is consistent with recent clinical studies suggesting that IV lidocaine may cause airway narrowing in asthmatics. Practitioners should be aware of this potential complication.

Previous study on racemic SPFF [2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride], a novel beta2-adrenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher beta2-adrenoceptor selectivity. On the basis of this study, we compared the pharmacological properties of SPFF and its enantiomers ((-)-SPFF and (+)-SPFF) in guinea pigs taking isoprenaline or salbutamol (SAB) as referenced drugs. For the relaxation of both normal and precontracted trachea strips in vitro, (-)-SPFF was found more potent than (+/-)-SPFF or (+)-SPFF. Moreover, we confirmed that the bronchodilator effect of (-)- and (+)-enantiomers were due to activation of the beta2-adrenoceptor because this effect was antagonized by a specific beta2-adrenoceptor antagonist, ICI-118551, with similar pA2 values to those of (+/-)-SPFF. Radioligand binding assay revealed that affinity of (-)-enantiomer to beta2-adrenoceptor was 6 and 164 fold greater than that of (+/-)- and (+)-SPFF, respectively. In addition, isomeric difference of overall selectivity between (-)-SPFF and (+)-SPFF was 10.7 fold for lung versus atria. (-)-SPFF displayed almost the same protective effect against bronchospasm induced by histamine-acetylcholine aerosol in conscious guinea pigs as (+/-)-SPFF did. However, the latent time of (+)-SPFF (1 mg.kg(-1)) was significantly shorter than that of (+/-)- and (-)-SPFF at the same doses. Finally, in the inhibition of histamine-induced increase of pulmonary resistance (RL) in anesthetized guinea pigs, (-)-SPFF was 1.3 and 3.5 times more potent than (+/-)- and (+)-SPFF. Correspondingly, in inhibiting the decrease of pulmonary compliance (CL) , the potencies of (-)- and (+)-enantiomers were approximately equivalent to that of (+/-)-SPFF. Furthermore, a study on the long-lasting action of the test drugs had shown that the effects of (-)-SPFF (30 microg.kg(-1)), (+/-)-SPFF (30 microg.kg(-1)) and (+)-SPFF (100 microg.kg(-1)) in inhibiting the increase of RL all lasted for 4 h. Nevertheless, the effects of (-)- and (+)-enantiomers were slightly lower 4 h after intraduodenal administration in inhibiting the decrease of CL. In conclusion, (-)-SPFF may be beneficial for the treatment of asthma because of its more potent efficacy and higher adrenoceptor affinity than (+/-)- or (+)-SPFF.

A standardized aqueous extract (AE) and a purified fraction (BuF) of Cecropia glaziovi Sneth leaves were tested in unrestrained guinea pigs challenged with histamine. Changes of the respiratory pressure and rate were recorded in a whole body plethysmograph before and after treatment. The concentration of histamine necessary to produce bronchospasm was increased by five-fold following administration of AE (1.0 g/kg p.o.), and by two-fold after treatment with the semi-purified procyanidin/flavonoids enriched BuF (0.1 g/kg p.o.). Both effects were blocked by previous treatment with propranolol (10.0 mg/kg i.p.). In vitro incubation of BuF (0.1-1.0 mg/ml) decreased by 13-55% the maximal response of guinea pig tracheal muscle to histamine, without significant change of EC50. The results confirmed old reports on the useful pulmonary effects of Cecropia extracts. The bronchodilation observed in vivo seems to be related to beta-adrenergic activity observed in vitro only with high concentrations of the purified extract.

Background: Delivery of tobramycin by inhalation to the lungs of patients with cystic fibrosis (CF) who are infected with Pseudomonas aeruginosa has been proven to be effective and safe. The aerosol administration allows high concentrations of tobramycin to be delivered to the site of infection with limited systemic absorption. In rare patients, systemic absorption of inhaled tobramycin may be significant enough to produce toxic effects, such as renal and vestibular toxicities., Case Presentation: We report a patient with CF who developed recurrent eosinophilia and severe persistent bronchospasm following repeated administration of preservative-free tobramycin by inhalation, beginning at 16 months of age. Also, he developed similar signs and symptoms when he was administered tobramycin intravenously on one occasion at 5 1/2 years. The patient had a history of environmental allergies. Temporal sequence of his signs and symptoms after each administration of tobramycin (similar to re-challenge testing), and his improvement after discontinuation of the drug strongly suggest an adverse drug reaction., Conclusion: Hypersensitivity reaction should be considered in patients who develop recurrent eosinophilia and deterioration of pulmonary function following the use of tobramycin by inhalation or by intravenous administration.

Daily nebulized colistin therapy has been used as maintenance therapy for patients with chronic Pseudomonas aeruginosa infection and in treatment protocols aimed at eradicating early P aeruginosa infection. Colistin-induced nephrotoxicity and mild neurotoxic effects have been described but hypersensitivity reactions are rare. However, bronchial constriction has been reported associated with the inhalation of the antibiotic. We report the case of a 63-year-old man who had been diagnosed with bronchiectasis and bronchopleural fistula and who developed severe bronchospasm when using nebulized colistin. A skin prick test (80 mg/mL) with colistin was performed and was negative. An intradermal test was not performed due to its possible irritant effect. As our patient suffered from a tobramycin-resistant P aeruginosa infection, we started a procedure to induce tolerance to 80 mg colistin (8 mg, 16 mg, 24 mg, 32 mg, 40 mg, 80 mg) nebulized in 30-minutes-intervals. No changes in forced expiratory volume in 1 second values were observed and the patient continues on treatment twice daily after the tolerance induction with no new episodes of bronchospasm. We report the first successful procedure to induce tolerance to colistin after escalating doses of inhaled colistin.

Background: We have shown that intravenous adenosine in normal subjects does not cause bronchospasm, but causes dyspnea, most likely by an effect on vagal C fibers in the lungs [Burki et al. J Appl Physiol 2005; 98:180-5]. Since airways inflammation and bronchial hyperreactivity are features of asthma, it is possible that intravenous adenosine may be associated with an increased intensity of dyspnea, and may cause bronchospasm, as noted anecdotally in previous reports., Methods: We compared the effects of placebo and 10 mg intravenous adenosine, in 6 normal and 6 asthmatic subjects., Results: Placebo injection had no significant (p > 0.05) effect on the forced expiratory spirogram, heart rate, minute ventilation (Ve), or respiratory sensation. Similarly, adenosine injection caused no significant changes (p > 0.05) in the forced expiratory spirogram; however, there was a rapid development of dyspnea as signified visually on a modified Borg scale, and a significant (p < 0.05) tachycardia in each subject (Asthmatics +18%, Normals + 34%), and a significant (p < 0.05) increase in Ve (Asthmatics +93%, Normals +130%). The intensity of dyspnea was significantly greater (p < 0.05) in the asthmatic subjects., Conclusion: These data indicate that intravenous adenosine does not cause bronchospasm in asthmatic subjects, and supports the concept that adenosine-induced dyspnea is most likely secondary to stimulation of vagal C fibers in the lungs. The increased intensity of adenosine-induced dyspnea in the asthmatic subjects suggests that airways inflammation may have sensitized the vagal C fibers.

Despite widespread use for treatment of asthma and allergies, glucocorticoids may cause allergic reactions, even anaphylaxis. The incidence of adverse reactions to systemic glucocorticoids is 0.3%. The most commonly reported corticosteroids causing anaphylaxis like reactions are hydrocortisone, prednisone, and methylprednisolone. Most authors agree that allergic reactions to systemic corticosteroids are possibly immunoglobulin E mediated. We report a patient with asthma, aspirin allergy, and nasal polyps who developed bronchospasm following the administration of intravenous methylprednisolone sodium succinate during an acute asthmatic attack. We discuss the differential diagnosis of worsening asthma despite adequate treatment, and suggest corticosteroid-induced bronchospasm in our patient. Corticosteroid-induced bronchospasm should be considered when asthmatics fail to improve, or frankly deteriorate with systemic corticosteroid therapy, particularly when a history of aspirin allergy is present. TEACHING POINT: Know the differential diagnosis for worsening of asthma despite adequate treatment. Consider corticosteroid-induced bronchospasm when asthmatics fail to improve, or frankly deteriorate with systemic corticosteroid therapy. Corticosteroid-induced bronchospasm is more commonly seen in asthmatics with a history of aspirin allergy.

Introduction: Partial assist ventilation reduces work of breathing in patients with bronchospasm; however, it is not clear which components of the ventilatory cycle contribute to this process. Theoretically, expiratory positive airway pressure (EPAP), by reducing expiratory breaking, may be as important as inspiratory positive airway pressure (IPAP) in reducing work of breathing during acute bronchospasm., Method: We compared the effects of 10 cmH2O of IPAP, EPAP, and continuous positive airwaypressure (CPAP) on inspiratory work of breathing and end-expiratory lung volume (EELV) in a canine model of methacholine-induced bronchospasm., Results: Methacholine infusion increased airway resistance and work of breathing. During bronchospasm IPAP and CPAP reduced work of breathing primarily through reductions in transdiaphragmatic pressure per tidal volume (from 69.4 +/- 10.8 cmH2O/l to 45.6 +/- 5.9 cmH2O/l and to 36.9 +/- 4.6 cmH2O/l, respectively; P < 0.05) and in diaphragmatic pressure-time product (from 306 +/- 31 to 268 +/- 25 and to 224 +/- 23, respectively; P < 0.05). Pleural pressure indices of work of breathing were not reduced by IPAP and CPAP. EPAP significantly increased all pleural and transdiaphragmatic work of breathing indices. CPAP and EPAP similarly increased EELV above control by 93 +/- 16 ml and 69 +/- 12 ml, respectively. The increase in EELV by IPAP of 48 +/- 8 ml (P < 0.01) was significantly less than that by CPAP and EPAP., Conclusion: The reduction in work of breathing during bronchospasm is primarily induced by the IPAP component, and that for the same reduction in work of breathing by CPAP, EELV increases more.

We present an interesting case of profound bronchospasm that we postulate was caused by injection of ethanol during embolization of a left transverse sinus dural fistula. There is excellent documentation in the literature of the development of transient pulmonary hypertension and decreased right-side cardiac output following embolization with this agent; however, there have been only anecdotal reports of a temporal relationship between ethanol embolization and bronchospasm. We present this case that occurred on the third ethanol embolization treatment series.