INTRODUCTION: Magnesium sulfate has been extensively used to treat asthma exacerbations, but its efficacy remains questionable in the chronic obstructive pulmonary disease (COPD) population. The aim of the study was to compare the efficacy of intravenous (IV) magnesium sulfate in COPD. A systemic review search was conducted on PubMed, Embase, and the Central Cochrane Registry. Randomized clinical trials were included with magnesium sulfate as an intervention arm in the COPD population.
MATERIALS AND METHODS: For continuous variables, standardized mean difference (SMD) and difference in means (MD) were calculated. For discrete variables, the Mantel-Haenszel (MH) odds ratio was used. For effect sizes, a confidence interval of 95% was used. A p-value of less than 0.05 was used for statistical significance. Analysis was done using both random and fixed effect models. Heterogeneity was evaluated using the I² statistic.
RESULTS: Seven studies were included in the final analysis. In patients with acute exacerbations of COPD treated with IV magnesium, a significant increase in forced expiratory volume in one second (FEV₁) was observed (MD = 2.537 [0.717 to 4.357], p = 0.006), as well as in peak expiratory flow rate (PEFR) (SMD = 1.073 [0.748 to 1.397], p < 0.001) using the fixed model. Similarly, residual volume decreased significantly in the IV magnesium group (MD = -0.470 [-0.884 to -0.056], p = 0.026). The hospitalization rate was also lower in the magnesium group, (MH odds ratio 0.453 [0.233 to 0.882], p = 0.020). No statistically significant difference was noted in FEV₁ in the stable COPD population.
CONCLUSION: IV magnesium was associated with a favorable deviation of FEV1 and PEFR, decreased residual volume, and decreased odds of admission in the COPD exacerbation population. Therefore, magnesium sulfate can be used as an adjunctive therapy in the treatment of acute exacerbations of COPD.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic and progressive disease, often punctuated by recurrent flare-ups or exacerbations. Magnesium sulfate, having a bronchodilatory effect, may have a potential role as an adjunct treatment in COPD exacerbations. However, comprehensive evidence of its effects is required to facilitate clinical decision-making.
OBJECTIVES: To assess the effects of magnesium sulfate for acute exacerbations of chronic obstructive pulmonary disease in adults.
SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization (WHO) trials portal, EU Clinical Trials Register and Iranian Registry of Clinical Trials. We also searched the proceedings of major respiratory conferences and reference lists of included studies up to 2 August 2021.
SELECTION CRITERIA: We included single- or double-blind parallel-group randomised controlled trials (RCTs) assessing magnesium sulfate in adults with COPD exacerbations. We excluded cross-over trials.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias. The primary outcomes were: hospital admissions (from the emergency room); need for non-invasive ventilation (NIV), assisted ventilation or admission to intensive-care unit (ICU); and serious adverse events. Secondary outcomes were: length of hospital stay, mortality, adverse events, dyspnoea score, lung function and blood gas measurements. We assessed confidence in the evidence using GRADE methodology. For missing data, we contacted the study investigators.
MAIN RESULTS: We identified 11 RCTs (10 double-blind and 1 single-blind) with a total 762 participants. The mean age of participants ranged from 62 to 76 years. Trials were single- or two-centre trials conducted in Iran, New Zealand, Nepal, Turkey, the UK, Tunisia and the USA between 2004 and 2018. We judged studies to be at low or unclear risk of bias for most of the domains. Three studies were at high risk for blinding and other biases. Intravenous magnesium sulfate versus placebo Seven studies (24 to 77 participants) were included. Fewer people may require hospital admission with magnesium infusion compared to placebo (odds ratio (OR) 0.45, 95% CI 0.23 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) = 7; 3 studies, 170 participants; low-certainty evidence). Intravenous magnesium may result in little to no difference in the requirement for non-invasive ventilation (OR 0.74, 95% CI 0.31 to 1.75; very low-certainty evidence). There were no reported cases of endotracheal intubation (2 studies, 107 participants) or serious adverse events (1 study, 77 participants) in either group. Included studies did not report intensive care unit (ICU) admission or deaths. Magnesium infusion may reduce the length of hospital stay by a mean difference (MD) of 2.7 days (95% CI 4.73 days to 0.66 days; 2 studies, 54 participants; low-certainty evidence) and improve dyspnoea score by a standardised mean difference of -1.40 (95% CI -1.83 to -0.96; 2 studies, 101 participants; low-certainty evidence). We were uncertain about the effect of magnesium infusion on improving lung function or oxygen saturation. For all adverse events, the Peto OR was 0.14 (95% CI 0.02 to 1.00; 102 participants); however, the event rate was too low to reach a robust conclusion. Nebulised magnesium sulfate versus placebo Three studies (20 to 172 participants) were included. Magnesium inhalation may have little to no impact on hospital admission (OR 0.77, 95% CI 0.21 to 2.82; very low-certainty evidence) or need for ventilatory support (NIV or mechanical ventilation) (OR 0.33, 95% CI 0.01 to 8.20; very low-certainty evidence). It may result in fewer ICU admissions compared to placebo (OR 0.39, 95% CI 0.15 to 1.00; very low-certainty evidence) and improvement in dyspnoea (MD -14.37, 95% CI -26.00 to -2.74; 1 study, 20 participants; very low-certainty evidence). There were no serious adverse events reported in either group. There was one reported death in the placebo arm in one trial, but the number of participants was too small for a conclusion. There was limited evidence about the effect of magnesium inhalation on length of hospital stay, lung function outcomes or oxygen saturation. Included studies did not report adverse events. Magnesium sulfate versus ipratropium bromide A single study with 124 participants assessed nebulised magnesium sulfate plus intravenous magnesium infusion versus nebulised ipratropium plus intravenous normal saline. There was little to no difference between these groups in terms of hospital admission (OR 1.62, 95% CI 0.78 to 3.37), endotracheal intubation (OR 1.69, 95% CI 0.61 to 4.71) and length of hospital stay (MD 1.10 days, 95% CI -0.22 to 2.42), all with very low-certainty evidence. There were no data available for non-invasive ventilation, ICU admission and serious adverse events. Adverse events were not reported. AUTHORS' CONCLUSIONS: Intravenous magnesium sulfate may be associated with fewer hospital admissions, reduced length of hospital stay and improved dyspnoea scores compared to placebo. There is no evidence of a difference between magnesium infusion and placebo for NIV, lung function, oxygen saturation or adverse events. We found no evidence for ICU admission, endotracheal intubation, serious adverse events or mortality. For nebulised magnesium sulfate, we are unable to draw conclusions about its effects in COPD exacerbations for most of the outcomes. Studies reported possibly lower ICU admissions and a lesser degree of dyspnoea with magnesium inhalation compared to placebo; however, larger studies are required to yield a more precise estimate for these outcomes. Similarly, we could not identify any robust evidence for magnesium sulfate compared to ipratropium bromide. Future well-designed multicentre trials with larger samples are required, including subgroups according to severity of exacerbations and COPD phenotypes.
OBJECTIVE: Corticosteroids have important effects on intermediate outcomes in critically ill patients, but their effect on survival is unknown. The objective of this meta-analysis was to analyze the effect on mortality of corticosteroids in critical and perioperative settings.
DESIGN: A meta-analysis of randomized trials.
SETTING: PubMed, Embase, BioMed Central, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched to February 1, 2018, for randomized trials comparing corticosteroids with placebo or standard care.
PARTICIPANTS: Critically ill or surgical adult patients.
INTERVENTIONS: Corticosteroids compared with placebo or standard care.
MEASUREMENTS AND MAIN RESULTS: A total of 44,553 patients from 135 studies were included. Overall, mortality in the corticosteroid group and in the control group were similar (16% v 16%; p = 0.9). Subanalyses identified a beneficial effect of corticosteroids on survival in patients with respiratory system diseases (9% v 13%; p < 0.001) and bacterial meningitis (28% v 32%; p= 0.04), and a detrimental effect on survival in patients with traumatic brain injury (22% v 19%; p < 0.001). No differences in mortality were found in patients with cardiac diseases (7% v 6%; p = 0.7), in patients undergoing cardiac surgery (2.8% v 3.2% p = 0.14), and when treatment duration or patient age were considered.
CONCLUSIONS: This meta-analysis documents the safety of corticosteroids in the overall critically ill population with the notable exception of brain injury patients, a setting where the authors confirmed their detrimental effect on survival. A possible beneficial effect of corticosteroids on survival was found among patients with respiratory diseases and in patients with bacterial meningitis.
BACKGROUND: Many patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However, the value of antibiotics remains uncertain, as systematic reviews and clinical trials have shown conflicting results.
OBJECTIVES: To assess effects of antibiotics on treatment failure as observed between seven days and one month after treatment initiation (primary outcome) for management of acute COPD exacerbations, as well as their effects on other patient-important outcomes (mortality, adverse events, length of hospital stay, time to next exacerbation).
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, MEDLINE, Embase, and other electronically available databases up to September 2018.
SELECTION CRITERIA: We sought to find randomised controlled trials (RCTs) including people with acute COPD exacerbations comparing antibiotic therapy and placebo and providing follow-up of at least seven days.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened references and extracted data from trial reports. We kept the three groups of outpatients, inpatients, and patients admitted to the intensive care unit (ICU) separate for benefit outcomes and mortality because we considered them to be clinically too different to be summarised as a single group. We considered outpatients to have a mild to moderate exacerbation, inpatients to have a severe exacerbation, and ICU patients to have a very severe exacerbation. When authors of primary studies did not report outcomes or study details, we contacted them to request missing data. We calculated pooled risk ratios (RRs) for treatment failure, Peto odds ratios (ORs) for rare events (mortality and adverse events), and mean differences (MDs) for continuous outcomes using random-effects models. We used GRADE to assess the quality of the evidence. The primary outcome was treatment failure as observed between seven days and one month after treatment initiation.
MAIN RESULTS: We included 19 trials with 2663 participants (11 with outpatients, seven with inpatients, and one with ICU patients).For outpatients (with mild to moderate exacerbations), evidence of low quality suggests that currently available antibiotics statistically significantly reduced the risk for treatment failure between seven days and one month after treatment initiation (RR 0.72, 95% confidence interval (CI) 0.56 to 0.94; I² = 31%; in absolute terms, reduction in treatment failures from 295 to 212 per 1000 treated participants, 95% CI 165 to 277). Studies providing older antibiotics not in use anymore yielded an RR of 0.69 (95% CI 0.53 to 0.90; I² = 31%). Evidence of low quality from one trial in outpatients suggested no effects of antibiotics on mortality (Peto OR 1.27, 95% CI 0.49 to 3.30). One trial reported no effects of antibiotics on re-exacerbations between two and six weeks after treatment initiation. Only one trial (N = 35) reported health-related quality of life but did not show a statistically significant difference between treatment and control groups.Evidence of moderate quality does not show that currently used antibiotics statistically significantly reduced the risk of treatment failure among inpatients with severe exacerbations (i.e. for inpatients excluding ICU patients) (RR 0.65, 95% CI 0.38 to 1.12; I² = 50%), but trial results remain uncertain. In turn, the effect was statistically significant when trials included older antibiotics no longer in clinical use (RR 0.76, 95% CI 0.58 to 1.00; I² = 39%). Evidence of moderate quality from two trials including inpatients shows no beneficial effects of antibiotics on mortality (Peto OR 2.48, 95% CI 0.94 to 6.55). Length of hospital stay (in days) was similar in antibiotic and placebo groups.The only trial with 93 patients admitted to the ICU showed a large and statistically significant effect on treatment failure (RR 0.19, 95% CI 0.08 to 0.45; moderate-quality evidence; in absolute terms, reduction in treatment failures from 565 to 107 per 1000 treated participants, 95% CI 45 to 254). Results of this trial show a statistically significant effect on mortality (Peto OR 0.21, 95% CI 0.06 to 0.72; moderate-quality evidence) and on length of hospital stay (MD -9.60 days, 95% CI -12.84 to -6.36; low-quality evidence).Evidence of moderate quality gathered from trials conducted in all settings shows no statistically significant effect on overall incidence of adverse events (Peto OR 1.20, 95% CI 0.89 to 1.63; moderate-quality evidence) nor on diarrhoea (Peto OR 1.68, 95% CI 0.92 to 3.07; moderate-quality evidence).
AUTHORS' CONCLUSIONS: Researchers have found that antibiotics have some effect on inpatients and outpatients, but these effects are small, and they are inconsistent for some outcomes (treatment failure) and absent for other outcomes (mortality, length of hospital stay). Analyses show a strong beneficial effect of antibiotics among ICU patients. Few data are available on the effects of antibiotics on health-related quality of life or on other patient-reported symptoms, and data show no statistically significant increase in the risk of adverse events with antibiotics compared to placebo. These inconsistent effects call for research into clinical signs and biomarkers that can help identify patients who would benefit from antibiotics, while sparing antibiotics for patients who are unlikely to experience benefit and for whom downsides of antibiotics (side effects, costs, and multi-resistance) should be avoided.
BACKGROUND: Current guidelines recommend that patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) should be treated with systemic corticosteroid for seven to 14 days. Intermittent systemic corticosteroid use is cumulatively associated with adverse effects such as osteoporosis, hyperglycaemia and muscle weakness. Shorter treatment could reduce adverse effects.
OBJECTIVES: To compare the efficacy of short-duration (seven or fewer days) and conventional longer-duration (longer than seven days) systemic corticosteroid treatment of adults with acute exacerbations of COPD.
SEARCH METHODS: Searches were carried out using the Cochrane Airways Group Specialised Register of Trials, MEDLINE and CENTRAL (Cochrane Central Register of Controlled Trials) and ongoing trials registers up to March 2017.
SELECTION CRITERIA: Randomised controlled trials comparing different durations of systemic corticosteroid defined as short (i.e. seven or fewer days) or longer (i.e. longer than seven days). Other interventions—bronchodilators and antibiotics—were standardised. Studies with participants requiring assisted ventilation were excluded.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration.
MAIN RESULTS: Eight studies with 582 participants met the inclusion criteria, of which five studies conducted in hospitals with 519 participants (range 28 to 296) contributed to the meta-analysis. Mean ages of study participants were 65 to 73 years, the proportion of male participants varied (58% to 84%) and COPD was classified as severe or very severe. Corticosteroid treatment was given at equivalent daily doses for three to seven days for short-duration treatment and for 10 to 15 days for longer-duration treatment. Five studies administered oral prednisolone (30 mg in four, tapered in one), and two studies provided intravenous corticosteroid treatment. Studies contributing to the meta-analysis were at low risk of selection, performance, detection and attrition bias. In four studies we did not find a difference in risk of treatment failure between short-duration and longer-duration systemic corticosteroid treatment (n = 457; odds ratio (OR) 0.72, 95% confidence interval (CI) 0.36 to 1.46)), which was equivalent to 22 fewer per 1000 for short-duration treatment (95% CI 51 fewer to 34 more). No difference in risk of relapse (a new event) was observed between short-duration and longer-duration systemic corticosteroid treatment (n = 457; OR 1.04, 95% CI 0.70 to 1.56), which was equivalent to nine fewer per 1000 for short-duration treatment (95% CI 68 fewer to 100 more). Time to the next COPD exacerbation did not differ in one large study that was powered to detect non-inferiority and compared five days versus 14 days of systemic corticosteroid treatment (n = 311; hazard ratio 0.95, 95% CI 0.66 to 1.37). In five studies no difference in the likelihood of an adverse event was found between short-duration and longer-duration systemic corticosteroid treatment (n = 503; OR 0.89, 95% CI 0.46 to 1.69, or nine fewer per 1000 (95% CI 44 fewer to 51 more)). Length of hospital stay (n = 421; mean difference (MD) -0.61 days, 95% CI -1.51 to 0.28) and lung function at the end of treatment (n = 185; MD FEV1 -0.04 L; 95% CI -0.19 to 0.10) did not differ between short-duration and longer-duration treatment.
AUTHORS' CONCLUSIONS: Information from a new large study has increased our confidence that five days of oral corticosteroids is likely to be sufficient for treatment of adults with acute exacerbations of COPD, and this review suggests that the likelihood is low that shorter courses of systemic corticosteroids (of around five days) lead to worse outcomes than are seen with longer (10 to 14 days) courses. We graded most available evidence as moderate in quality because of imprecision; further research may have an important impact on our confidence in the estimates of effect or may change the estimates. The studies in this review did not include people with mild or moderate COPD; further studies comparing short-duration systemic corticosteroid versus conventional longer-duration systemic corticosteroid for treatment of adults with acute exacerbations of COPD are required.
Magnesium sulfate has been extensively used to treat asthma exacerbations, but its efficacy remains questionable in the chronic obstructive pulmonary disease (COPD) population. The aim of the study was to compare the efficacy of intravenous (IV) magnesium sulfate in COPD. A systemic review search was conducted on PubMed, Embase, and the Central Cochrane Registry. Randomized clinical trials were included with magnesium sulfate as an intervention arm in the COPD population.
MATERIALS AND METHODS:
For continuous variables, standardized mean difference (SMD) and difference in means (MD) were calculated. For discrete variables, the Mantel-Haenszel (MH) odds ratio was used. For effect sizes, a confidence interval of 95% was used. A p-value of less than 0.05 was used for statistical significance. Analysis was done using both random and fixed effect models. Heterogeneity was evaluated using the I² statistic.
RESULTS:
Seven studies were included in the final analysis. In patients with acute exacerbations of COPD treated with IV magnesium, a significant increase in forced expiratory volume in one second (FEV₁) was observed (MD = 2.537 [0.717 to 4.357], p = 0.006), as well as in peak expiratory flow rate (PEFR) (SMD = 1.073 [0.748 to 1.397], p < 0.001) using the fixed model. Similarly, residual volume decreased significantly in the IV magnesium group (MD = -0.470 [-0.884 to -0.056], p = 0.026). The hospitalization rate was also lower in the magnesium group, (MH odds ratio 0.453 [0.233 to 0.882], p = 0.020). No statistically significant difference was noted in FEV₁ in the stable COPD population.
CONCLUSION:
IV magnesium was associated with a favorable deviation of FEV1 and PEFR, decreased residual volume, and decreased odds of admission in the COPD exacerbation population. Therefore, magnesium sulfate can be used as an adjunctive therapy in the treatment of acute exacerbations of COPD.
