Ketamine for Adults with Severe Asthma Exacerbation: A Systematic Review and Meta-analysis

BACKGROUND: Severe asthma mandates careful attention and timely management, and the benefit of ketamine in severe asthma exacerbations in adult patients require further exploration. METHODS: We conducted a systematic review and meta-analysis of the use of ketamine in cases of acute asthma exacerbation in adults. We searched PubMed, Google Scholar, Cochrane databases, and gray literature (ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform); we also searched the reference lists of included articles and any systematic reviews and meta-analyses identified therein. Our search covered the period from 1963 to August 20, 2021. Search terms were “ketamine” AND “asthma”. RESULTS: Of 25 540 articles, two studies were included in the analysis. The total number of patients included in the studies was 136 (68 in the ketamine groups and 68 in the placebo group). The pooled effect size was 0.30 (95% CI: -0.04, 0.63) favouring ketamine over placebo, p=0.08, (I2=0%, p=0.39). A paired t-test revealed that ketamine improved the mean peak expiratory flow rate (PEFR) from 242.4 (SD=146.23) to 286.95 (SD=182.22), p=0.33, representing an 18.38% improvement. CONCLUSION: Ketamine can induce a 30% improvement in PEFR, representing a small positive effect in the treatment of acute severe asthma exacerbation in the emergency department (ED). The improvement was not statistically significant; nonetheless, since the improvement could be as great as 63% versus only a 4% possibility of no benefit/harm, the benefit appears to considerably outweigh any harm.

Efficacy and safety of as-needed albuterol/budesonide versus albuterol in adults and children aged ≥4 years with moderate-to-severe asthma: rationale and design of the randomised, double-blind, active-controlled MANDALA study

IntroductionUncontrolled asthma is associated with substantial morbidity. While fast-acting bronchodilators provide quick relief from asthma symptoms, their use as rescue fails to address the underlying inflammation. Combining a short-acting beta2-agonist, such as albuterol (salbutamol), with an inhaled corticosteroid, such as budesonide, in a single inhaler as rescue therapy could help control both bronchoconstriction and inflammation, and reduce the risk of asthma exacerbations.Methods and analysisThe Phase 3 MANDALA study was designed to determine the efficacy of albuterol in combination with budesonide (albuterol/budesonide 180/160 µg or 180/80 µg, two actuations of 90/80 µg or 90/40 µg, respectively) versus albuterol (180 µg, two actuations of 90 µg) as rescue therapy in adult, adolescent and paediatric patients with moderate-to-severe asthma. This event-driven study enrolled symptomatic patients (3000 adults/adolescents and 100 children aged 4–11 years) who experienced ≥1 severe asthma exacerbation in the previous year and were receiving maintenance therapy for ≥3 months prior to study entry. The primary efficacy endpoint was time-to-first severe asthma exacerbation.Ethics and disseminationThe study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice and the applicable regulatory requirements.Trial registrationNCT03769090.

Sputum metabolomic profiling revels metabolic pathways and signatures associated with inflammatory phenotypes in patients with asthma

Background: The molecular links between metabolism and inflammation that drive different inflammatory phenotypes in asthma are poorly understood. Objectives: To identify the metabolic signatures and underlying molecular pathways of different inflammatory asthma phenotypes. Method: In the discovery set (n=119), untargeted ultra-high performance liquid chromatography–mass spectrometry (UHPLC-MS) were applied to characterize the induced sputum metabolic profiles from asthmatic patients classified by different inflammatory phenotypes using orthogonal partial least-squares discriminant analysis (OPLS-DA) and pathway topology enrichment analysis. In the validation set (n = 114), differential metabolites were selected to perform targeted quantification. Correlations between targeted metabolites and clinical indexes in asthma patients were analyzed. Logistic and negative binomial regression models were established to assess the association between metabolites and severe asthma exacerbation. Results: 77 differential metabolites were identified in the discovery set. Pathway topology analysis uncovered that histidine metabolism, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, linoleic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis were involved in the pathogenesis of different asthma phenotypes. In the validation set, 24 targeted quantification metabolites were significantly differentially expressed between asthma inflammatory phenotypes. Finally, adenosine 5’-monophosphate (RRadj = 1.000, 95%CI = [1.000, 1.000], P = 0.050), allantoin (RRadj = 1.000, 95%CI = [1.000, 1.000], P = 0.043) and nicotinamide (RRadj = 1.001, 95%CI = [1.000, 1.002], P = 0.021) were demonstrated to predict severe asthma exacerbation rate ratios. Conclusions: Different inflammatory asthma phenotypes have specific metabolic profiles in induced sputum. The potential metabolic signatures may serve as identification and therapeutic target in different inflammatory asthma phenotypes.

Typical Antipsychotics Increase Risk of Severe Exacerbation in Asthma Patients– A Nationwide Population-Based Cohort Study

Background:Severe asthma exacerbation reduces patients’ life quality, results in visits to the emergency department (ED) and hospitalization, and incurs additional medical costs. Antipsychotics block receptors with bronchodilation function; however, the effects of antipsychotics use on severe asthma exacerbation are unknown. This study aimed to investigate the effects of antipsychotics on asthma-related ED visits and hospitalizations.Methods:This study used a case-crossover design. Using the 2003-2017 Taiwan National Health Insurance Reimbursement Database, we established a cohort of 18,657 adults with severe asthma exacerbation leading to ED visits or hospitalization. Univariate and multivariate conditional logistic regressions were conducted to explore the association of antipsychotics use with severe asthma exacerbation. Subgroup analyses of different classes, doses, receptor functions of antipsychotics and schizophrenia were also performed.Results:Antipsychotics use was associated with a higher risk of severe asthma exacerbation (adjusted odds ratio (OR): 1.27; 95% confidence interval (CI): 1.05-1.54; P = 0.013) compared with no use of antipsychotics. Use of typical antipsychotics increased the risk of severe asthma exacerbation (adjusted OR: 1.40, 95% CI: 1.10-1.79, P = 0.007), whereas use of atypical antipsychotics did not. There was a dose-dependent effect of antipsychotics (test for trend: P =0.025). Antipsychotics that block the M2 muscarinic or D2 dopaminergic receptor were associated with an increased risk of severe asthma exacerbation (adjusted OR: 1.39, 95% CI: 1.10-1.76, P = 0.007 and adjusted OR: 1.33, 95% CI: 1.08-1.63, P = 0.008, respectively).Conclusions: Use of typical antipsychotics is associated with a dose-dependent increased risk of severe asthma exacerbation. Physicians should thus weight the risk and benefit of prescribing high-dose typical antipsychotics for asthma patients.

Does the occurrence of a severe asthma exacerbation change the rate of subsequent events?

Background: Severe exacerbations requiring hospitalization are an important component of the natural history of asthma and a major source of its burden. Whether the occurrence of a severe exacerbation affects the rate of subsequent events has far-reaching implications in asthma management. Methods: Using the centralized administrative health databases of British Columbia, Canada (1997/01/01-2016/03/31), we created an incidence cohort of patients with at least one severe asthma exacerbation, defined as an episode of hospitalization with asthma as the primary diagnosis. We used an accelerated failure time joint frailty model for the time intervals between severe asthma exacerbations. Analyses were conducted separately for pediatric (< 14 years old) and adult (≥14 years old) patients. Results: There were 3,039 patients (mean age at baseline 6.4, 35% female) in the pediatric group and 5,459 patients (mean age at baseline 50.8, 68% female) in the adult group, with 16% and 15%, respectively, experiencing at least one severe asthma exacerbation during follow-up. The first follow-up severe asthma exacerbation was associated with an increase of 79% (95% CI: 15% - 186%) in the rate of the subsequent events for the pediatric group. The corresponding value was 186% (95% CI: 85% - 355%) for the adult group. For both groups, the effects of subsequent severe exacerbations were not statistically significant. Conclusion: Our findings suggest that among patients who have experienced their first severe asthma exacerbation, preventing the next event can drastically change the course of the disease and reduce the burden of future exacerbations.

Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: A meta-analysis

Background A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice. Objective To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents. Methods The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the earliest record date to September 2020 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO. Results Of the 1061 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66–0.95; p = 0.01; I2 = 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.73; 95% CI 0.60–0.88; p = 0.0009; I2 = 4%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50–0.96; p = 0.03; I2 = 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63–4.98). Conclusion IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. The very low to high quality of evidence indicated that future well-designed double-blind RCTs with large sample are needed for research on evaluating the effectiveness of IB + salbutamol treatment for asthma in children and adolescents.