Use Of Intravenous Magnesium Research Articles

Practicing What We Teach: Increasing Inhaler Use for Mild Asthma in the Pediatric Emergency Department.

Asthma is a leading cause of pediatric emergency department (ED) visits. A metered-dose inhaler and spacer (MDI-S) device is equivalent to and more cost effective than delivery by nebulization in the ED management of mild asthma exacerbations. We aimed to increase the use of albuterol MDI-S among patients with mild asthma exacerbations using a quality improvement framework. We evaluated albuterol use for mild asthma exacerbations between January 2019 and March 2020 in our pediatric EDs. Our primary outcome was the proportion of albuterol delivered through an MDI-S. Our process measure was the use of a new electronic order set. Balancing measures included ED length of stay, admission rates, and the use of intravenous magnesium. Interventions included forging multidisciplinary partnerships, revising clinical practice guidelines, establishing an electronic order set, and leading educational initiatives for clinicians. We demonstrated a center line shift of MDI-S use from 34.4% to 47.7%. The average length of stay, hospital admissions, and magnesium use were not affected by our interventions. Forging multidisciplinary partnerships, creating an electronic order set prioritizing albuterol MDI-S use, and educational initiatives led to a sustained increase in albuterol MDI-S use for mild asthma in our pediatric EDs.

The effect of intravenous magnesium on postoperative morphine consumption in noncardiac surgery: A systematic review and meta-analysis with trial sequential analysis.

Several studies suggest that systemic magnesium reduces postoperative opioid consumption and the intensity of pain, but others report conflicting results. The efficacy and safety profile of intravenous magnesium in noncardiac surgery remain uncertain. The aim of this review was to investigate the effect of intravenous magnesium on the consumption of postoperative morphine in the first 24 h in adults undergoing noncardiac surgery. Systematic review and meta-analysis with trial sequential analysis. MEDLINE, EMBASE, CENTRAL from their inception until January 2019. All randomised clinical trials comparing intravenous magnesium versus placebo in noncardiac surgery were systematically searched in the databases. Observational studies, case reports, case series and nonsystematic reviews were excluded. Fifty-one trials (n=3311) were included for quantitative meta-analysis. In comparison with placebo, postoperative morphine consumption at 24-h was significantly reduced in the magnesium group, with a mean difference [95% confidence interval (CI)] of -5.6 mg (-7.54 to -3.66, P < 0.001, I = 92%, level of evidence low). The trial sequential analysis for the effect of magnesium on postoperative morphine consumption was conclusive. Patients who received magnesium had a longer time to the first analgesia request [143 (103 to 183) min, P < 0.001, I = 99%, level of evidence low] and a lower incidence of shivering [0.26 (0.15 to 0.44), P < 0.001, I = 35%, level of evidence very low]. However, no significance differences were demonstrated in postoperative pain scores in the first 24 h (mean difference, 95% CI) -0.30 (-0.69 to 0.09, P = 0.13, I = 91%, level of evidence low), bradycardia (odds ratio, 95% CI) 1.13 (0.43 to 2.98, P = 0.80, I = 35%, level of evidence very low) and postoperative nausea and vomiting (odds ratio, 95% CI) 0.90 (0.67 to 1.22, P = 0.49, I = 25%, level of evidence moderate). The current meta-analysis demonstrates that the use of intravenous magnesium as part of multimodal analgesia may reduce morphine consumption in the first 24 h after surgery and delay the time to the first request for analgesia in patients undergoing noncardiac surgery. However, the included studies were of low-quality with substantial heterogeneity. CRD42018086846.

Parturient on Magnesium Infusion and Its Effectiveness as an Adjuvant Analgesic after Cesarean Delivery: A Retrospective Analysis.

Background Perioperative use of intravenous magnesium as part of multimodal analgesia has been increasing in recent years in an effort to decrease the use of opioids. The aim of this study was to evaluate the effectiveness of magnesium sulfate infusion in lowering analgesic requirement and decreasing the intensity of pain score after cesarean delivery. Methods Sixty-four patients who underwent cesarean delivery under spinal anesthesia were included in this medical record review: 32 patients received magnesium infusion after cesarean delivery for treatment of mild preeclampsia (Mg group); 32 patients received routine post-cesarean delivery care (control group). Primary outcome was total analgesic consumption and secondary was visual analogue scores (VAS) of pain in each group during the first 24 hours following delivery. These measures were compared using Student's t-tests and Mann-Whitney U-tests. Results Our study found that patients in the Mg group had significantly less requirement for analgesia than the control group. In the 24 h after cesarean delivery, the Mg group received significantly less intravenous ketorolac (the standard initial rescue analgesic agent) when compared to the control group (79 ± 23 mg vs. 90 ± 0 mg; P = 0.008). The Mg group also received significantly less intravenous morphine equivalents than the control group (median 5.0 (IRQ: 0.0 – 10.0) vs. 9.3 (IRQ: 6.0 – 21.1); P = 0.001) during the first 24 h after cesarean delivery. The Mg group also had significantly lower VAS pain scores than the control group (median 1.75 (IRQ: 0.4 – 2.6) vs. median 3.2 (IRQ: 2.3 – 4.5); P < 0.001). Conclusions Our results suggest that magnesium sulfate infusion decreases total analgesic requirements and lowers VAS pain scores during the first 24 h after cesarean delivery.

The effect of nebulised magnesium sulphate in the management of childhood moderate asthma exacerbations as adjuvant treatment

BackgroundAfter the bronchodilator effect of magnesium was shown, the use of magnesium in treatment of asthma exacerbations became common. With the results of recent studies, the use of intravenous magnesium in severe asthma exacerbations took its place. We aimed to examine the effects of adding isotonic magnesium sulphate instead of isotonic saline into nebulised salbutamol on the Modified Pulmonary Index Score (MPIS) and the hospitalisation rate in moderate asthma exacerbations. MethodsOur study population included 100 children age between 3 and 15 years with asthma admitted to emergency department due to moderate asthma exacerbations. The patients were randomised to placebo or magnesium, with 50 patients in each arm. All patients received 1mg/kg of systemic methylprednisolone at the beginning of treatment and thereafter received either nebulised salbutamol (0.15mg/kg/dose) and 1ml magnesium sulphate (15%)+1.5ml isotonic saline on three occasions at roughly 20min intervals (Magnesium group) or nebulised salbutamol (0.15mg/kg/dose) and 2.5ml isotonic saline mixture on three occasions at roughly 20min intervals (Placebo group). The MPIS of patients on 0th min, 20th min, 40th and 120th min were calculated and compared. The primary outcome was to compare MPIS values at the end of 120th min. ResultsBoth groups have similar demographic, allergic characteristics and baseline MPIS scores. When the MPIS scores in the 120th min and admission rates in the 200th min, there was no significant difference between the two groups. ConclusionsThe use of nebulised magnesium sulphate in moderate asthma exacerbation as adjuvant treatment showed no benefit to standard treatment in our study.

Effect of intravenous infusion of magnesium sulphate on postoperative analgesia in patients undergoing arthroscopic knee surgeries under spinal anaesthesia

Background: Magnesium sulphate is being used for postoperative pain relief intravenously, intrathecally and epidurally. Currently, it is also gaining popularity as an adjuvant in blocks. The objective of the study was aimed at the postoperative analgesic effects of magnesium sulphate when given as intravenous infusion in patients undergoing arthroscopic knee surgeries under spinal anaesthesia and to compare the postoperative analgesic effects of magnesium sulphate infusion in a study cohort who received magnesium sulphate with the control cohort who were not given magnesium sulphate and underwent arthroscopic knee surgeries under spinal anaesthesia.Methods: After obtaining ethical committee clearance and consent from the patients, 31 patients each were placed in study cohort and control cohort. Spinal anaesthesia was administered in the lateral decubitus position through the L3–4 or L4–5 interspace. Hyperbaric bupivacaine 0.5% solution with fentanyl 20 μg was injected intrathecally. After spinal anaesthesia, patients received magnesium sulphate 50 mg/kg for 15 min and then 15 mg/kg/hr by continuous intravenous infusion until the end of surgery. The other group did not receive magnesium sulphate infusion. Postoperative pain scores and postoperative analgesic consumption were the primary end points.Results: The results of the study reveal the efficacy of perioperative intravenous infusion of magnesium sulphate in prolonging the spinal block as well as reducing the postoperative pain scores without hemodynamic variability or side effects.Conclusions: Post-operative pain and analgesic consumption was reduced with the use of intravenous magnesium following spinal anaesthesia.

Intravenous Magnesium Sulphate for Analgesia after Caesarean Section: A Systematic Review.

Objective To summarise the evidence for use of intravenous magnesium for analgesic effect in caesarean section patients. Background Postcaesarean pain requires effective analgesia. Magnesium, an N-methyl-D-aspartate receptor antagonist and calcium-channel blocker, has previously been investigated for its analgesic properties. Methods A systematic search was conducted of PubMed, Scopus, MEDLINE, Cochrane Library, and Google Scholar databases for randomised-control trials comparing intravenous magnesium to placebo with analgesic outcomes in caesarean patients. Results Ten trials met inclusion criteria. Seven were qualitatively compared after exclusion of three for unclear bias risk. Four trials were conducted with general anaesthesia, while three utilised neuraxial anaesthesia. Five of seven trials resulted in decreased analgesic requirement postoperatively and four of seven resulted in lower serial visual analogue scale scores. Conclusions Adjunct analgesic agents are utilised to improve analgesic outcomes and minimise opioid side effects. Preoperative intravenous magnesium may decrease total postcaesarean rescue analgesia consumption with few side effects; however, small sample size and heterogeneity of methodology in included trials restricts the ability to draw strong conclusions. Therefore, given the apparent safety and efficacy of magnesium, its role as an adjunct analgesic in caesarean section patients should be further investigated with the most current anaesthetic techniques.

Modeling of Amiodarone Effect on Heart Rate Control in Critically Ill Patients with Atrial Tachyarrhythmias.

Amiodarone is the gold-standard medication to control heart rate in critically ill patients with atrial tachyarrhythmias (ATs); however, effective doses and covariates influencing its efficacy remain unknown. We therefore performed pharmacodynamic modeling of heart rate reduction induced by amiodarone in these patients. This observational study included 80 consecutive severely ill patients receiving amiodarone to treat ATs. A total of 1348 time-heart rate observations with 361 amiodarone dose administrations were analyzed during a period of up to 6days after hospital treatment initiation using a nonlinear mixed-effect model. Pretreatment with amiodarone before intensive care administration, paroxysmal versus persistent AT, catecholamine infusion, and fluid and magnesium loading were among the covariates assessed in the model. In case of paroxysmal AT in a patient not pretreated with amiodarone, a 300mg intravenous loading dose combined with an 800mg oral dose on the first day, followed by 800mg/day orally for 4days was effective in achieving a heart rate between 80 and 115bpm within the first day, and to maintain it during the next 4days. Corresponding doses were twice as high in patients with persistent AT. Use of intravenous magnesium (p<0.02) and fluid loading (p<0.02) was associated with an earlier and greater heart rate decrease, while use of dobutamine had an opposite influence (p<0.05). In critically ill patients with AT, the dose of amiodarone required to control heart rate is influenced by the type of AT and by other easily measurable conditions which may allow better individualization of amiodarone dosing.

The use of intravenous magnesium in non-preeclamptic pregnant women: fetal/neonatal neuroprotection.

To review the effect of intravenous magnesium in obstetrics on fetal/neonatal neuroprotection. A systematic review of published studies. Five randomized trials and 4 meta-analyses have shown a significant 32% reduction of cerebral palsy when administering magnesium sulfate in case of preterm delivery. The pathophysiologic mechanism is not fully unraveled: modulation of the inflammatory process, both in the mother and the fetus, and downregulation of neuronal stimulation seem to be involved. After long-term high-dose intravenous administration of magnesium, maternal and neonatal adverse effects such as maternal and neonatal hypotonia and osteoporosis and specific fetal/neonatal cerebral lesions have been described. In case of administration for less than 48 h at 1 g/h and a loading dose of 4 g, these toxic amounts are not achieved. American, Canadian and Australian guidelines recommend the use of intravenous magnesium in any threatening delivery at less than 32 weeks. The "number needed to treat" to avoid 1 cerebral palsy is between 15 and 35. Intravenous magnesium significantly reduces the risk for cerebral palsy in preterm birth. Open questions remain the optimal dosing schedule, whether or not repeating when delivery has been successfully postponed and a new episode of preterm labor occurs. Some concern has been raised on a too optimistic value for random error which might have led to over-optimistic conclusions in classic meta-analysis. Randomized trials comparing different doses and individual patient data meta-analysis might resolve these issues.

A Multi-Center Randomized Controlled Trial of Intravenous Magnesium for Sickle Cell Pain Crisis in Children

Introduction: There are approximately 18,000 hospitalizations and 75,000 hospitalization days annually in the United States for children experiencing sickle cell vasoocclusive crises. Despite advances in the management of other comorbidities of sickle cell disease, little has changed in the management of sickle cell pain crises. Magnesium, a known vasodilator, anti-inflammatory and pain reliever, has the potential to alter the pathophysiology of pain crises, shortening length of stay and decreasing opioid use. A previous pilot study showed IV magnesium shortened length of stay compared to historical controls. A randomized trial conducted in Canada showed no decrease in length of stay with the use of intravenous magnesium. In the MAGiC (MAGnesium for children in Crisis) study, we hypothesized that the addition of intravenous (IV) magnesium to standard therapy would shorten hospital length of stay, result in decreased opioid use and improve quality of life for pediatric patients hospitalized with sickle cell pain crises.Methods: The MAGiC study was a multi-center, randomized, double-blind, placebo-controlled trial of IV magnesium versus normal saline for the treatment of pediatric sickle cell pain crisis conducted at 8 sites. Participating sites were members of the Pediatric Emergency Care Applied Research Network (PECARN), and collaborations between Pediatric Emergency Medicine physicians and Pediatric sickle cell experts facilitated enrollment. Children aged 4 to 21 years, with hemoglobin SS or hemoglobin SB° thalassemia were eligible if they required inpatient hospitalization after failing emergency department (ED) management for pain. Enrollment occurred at 8 sites between December 2010 and December 2013, with a total of 217 eligible site enrollment months. Children received 40 mg/kg of IV magnesium every eight hours for a total of 6 doses or normal saline placebo of equivalent volume (1 ml/kg). Randomization was stratified by site, age and hydroxyurea use. The primary outcome was length of stay from the time of first drug infusion until 12 hours after the last IV opioid dose or time of discharge, whichever occurred first. Secondary outcomes included opioid use, recorded as morphine equivalents, and quality of life, as measured using the PedsQL Sickle cell disease specific module, fatigue module and generic module. Side effects, specifically hypotension, weakness, warmth on infusion, or the development of acute chest syndrome (ACS) were documented. Using an intention-to-treat analysis, we compared length of stay using a Van Elteren test, stratified by the same factors used to stratify randomization.Results: 208 children were enrolled. Four children were excluded prior to receipt of any study drug, resulting in 101 children receiving magnesium and 103 receiving placebo. The 2 groups were similar with respect to age, sex ,genotype, weight, history of ACS or asthma, previous hospitalizations within the past three years and days of pain prior to arrival. The median time from first ED opioid to first study drug infusion was 7.4 hours, similar between the two groups. The median (interquartile range) length of stay was 56.0 (27.0 - 109.0) hours in the magnesium group compared to 47.0 (24.0 - 99.0) hours in the placebo group, p = 0.264. Patients who received magnesium received 1.46 mg/kg of morphine equivalents compared to 1.28 mg/kg in the placebo group (p=0.11). Quality of life scores were similar between the two groups after 48 hours on study drug and one week after discharge (p > 0.10 at both time points). Safety analysis revealed no differences in hypotension (3% for magnesium versus 1% for placebo) or weakness (7% versus 4%) between the 2 groups. Of those who received magnesium, 26% reported warmth on infusion compared to 2% of children who received placebo, p < .0001. Other adverse events, serious adverse events, and rehospitalizations within 7 days were similar between the groups.Conclusion: Intravenous magnesium does not shorten length of stay, lessen opioid use or improve quality of life in children who require hospitalization for sickle cell pain crisis. Close collaboration between Pediatric Emergency Medicine physicians and Pediatric Hematologists allows for the successful enrollment of large numbers of children in an acute intervention trial for children with sickle cell disease. DisclosuresOff Label Use: magnesium for sickle cell pain crisis.

The acute management of asthma.

Patients presenting to the emergency department (ED) or clinic with acute exacerbation of asthma (AEA) can be very challenging varying in both severity and response to therapy. High-dose, frequent or continuous nebulized short-acting beta2 agonist (SABA) therapy that can be combined with a short-acting muscarinic antagonist (SAMA) is the backbone of treatment. When patients do not rapidly clinically respond to SABA/SAMA inhalation, the early use of oral or parenteral corticosteroids should be considered and has been shown to impact the immediate need for ICU admission or even the need for hospital admission. Adjunctive therapies such as the use of intravenous magnesium and helium/oxygen combination gas for inhalation and for driving a nebulizer to deliver a SABA and or SAMA should be considered and are best used early in the treatment plan if they are likely to impact the patients' clinical course. The use of other agents such as theophylline, leukotriene modifiers, inhaled corticosteroids, long-acting beta2 agonist, and long-acting muscarinic antagonist currently does not play a major role in the immediate treatment of AEA in the clinic or the ED but is an important therapeutic option for physicians to be aware of and to consider initiating at the time of discharge from clinic, hospital, or ED to reduce later clinical worsening and readmission to the ED and hospital. A comprehensive summary is provided of the currently available respiratory pharmaceuticals approved for asthma and other airway syndromes. Clinicians must be prepared to use the entire spectrum of medications available for the treatment of acute asthma exacerbations and the agents that should be initiated to prevent worsening or additional exacerbations. They need to be familiar with the major potential drug toxicities associated with their use.

Role of Per Operative Use of Intravenous Magnesium in Reducing the Incidence of Per and Post Operative Arrhythmias in Conventional Coronary Artery Bypass Graft Surgery

Introduction: Arrhythmias are not uncommon after Coronary Artery Bypass Graft (CABG) surgery. There is increasing evidence that Magnesium, the important intracellular cation plays a crucial role in preventing and terminating cardiac arrhythmias. Objectives: The aim of this study was to establish the role of peroperative use of intravenous Magnesium in reducing the incidence of per and postoperative arrhythmias in CABG surgery. Materials and methods: A total sixty (Group-I 30 and Group-II 30) patients of both sexes and different ages undergoing conventional CABG surgery under general anesthesia in CMH Dhaka from January 2009 to December 2011 were selected randomly. After induction, Group-I received 2 gm of Magnesium in 100 ml normal saline intravenously over a period of 30 minutes and Group-II received no Magnesium. Parameters recorded per and postoperatively were- aortic cross clamp time, Cardio Pulmonary Bypass (CPB) time, total surgery time, Heart Rate (HR), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and blood sample were collected on arrival to Cardiac Intensive Care Unit (CICU) and after 6, 12, and 24 hours. Results were expressed as mean ± SD (Standard Deviation) or in frequencies (percentage) as applicable. The results were analyzed by Student’s ‘t’ test. Results: Magnesium levels were significantly (p&lt;0.05) low in Group-II patients than that of Group-I. In Group-II patients, the fluctuations of HR, SBP and DBP were significantly (p&lt;0.05) more than that of Group-I. In Group-I patients incidence of arrhythmias were significantly (p&lt;0.05) less than that of Group-II. Conclusion: Low serum Magnesium levels are a frequent finding after conventional CABG surgery. This acute loss of Magnesium has been suggested as an etiology of many per and postoperative arrhythmias. This study revealed that peroperative administration of Magnesium provided a significant reduction in arrhythmias per and postoperatively. DOI: http://dx.doi.org/10.3329/jafmc.v9i1.18739 Journal of Armed Forces Medical College Bangladesh Vol.9(1) 2013: 105-114

Effect of continuous magnesium sulfate infusion on spinal block characteristics: A prospective study

Background:Spinal anesthesia is an established mode of anesthesia for lower limb orthopedic surgeries. The limitations of the technique are short duration of action and limited post-operative analgesia. Concomitant use of intravenous infusion of magnesium sulfate may have an effect on the block characteristics and duration of action of intrathecal bupivacaine.Methods:A total of 80 American Society of Anesthesiologists I and II patients, either sex, 20-60 years of age scheduled for elective orthopedic fixation of fracture of long bones of lower limbs under spinal anesthesia were included. Spinal anesthesia administered with 2.5 ml heavy bupivacaine mixed with 10 mcg fentanyl. The groups were then divided to receive an infusion of injection magnesium sulfate 50 mg/kg/h over 15 min followed by 15 mg/kg/h until the end of the surgery (Group M) and 15 ml of Normal Saline over 15 min followed by 100 ml/h until the end of surgery (Group S). Onset, duration of sensory and motor block and amount of post-operative analgesic were noted.Results:A total of 6 patients (Group M) and seven patients (Group S) had inadequate block and excluded from the study. Mean block height was T6. Time required to achieve block height was 8.82 min versus 7.42 min in Groups M and S respectively (P = 0.04). Mean duration of motor block was longer in group M (160.63 ± 17.76 min) compared with Group S (130.12 ± 20.70 min) (P = 0.000). Time for regression of sensory block to T12/L1was 206.88 ± 20.96 min (Group M) and 163.88 ± 15.46 min (Group S) (P = 0.000). Hemodynamic parameters were similar and statistically not significant. Need for first analgesic requirement was after 262.88 ± 21.11 min in group M and 193.25 ± 17.74 min in the group S (P = 0.000). Mean dosage of tramadol needed in first 24 h was less in group M (190 ± 30.38 mg vs. 265 ± 48.30 mg, P = 0.000).Conclusion:Use of intravenous magnesium with spinal anesthesia reduces post-operative pain and analgesic consumption.

Magnesium Use in Asthma Pharmacotherapy: A Pediatric Emergency Research Canada Study

To examine the use of intravenous magnesium in Canadian pediatric emergency departments (EDs) in children requiring hospitalization for acute asthma and association of administration of frequent albuterol/ipratropium and timely corticosteroids with hospitalization. Retrospective medical record review at 6 EDs of otherwise healthy children 2 to 17 years of age with acute asthma. Data were extracted on history, disease severity, and timing of ED stabilization treatments with inhaled albuterol, ipratropium, corticosteroids, and magnesium. Primary outcome was the proportion of hospitalized children given magnesium in the ED. Secondary outcome was the ED use of "intensive therapy" in hospitalized children, defined as 3 albuterol inhalations with ipratropium and corticosteroids within 1 hour of triage. A total of 19 (12.3%) of 154 hospitalized children received magnesium (95% confidence interval 7.1, 17.5) versus 2 of 962 discharged patients. Children given magnesium were more likely to have been previously admitted to ICU (odds ratio [OR] 11.2), hospitalized within the past year (OR 3.8), received corticosteroids before arrival (OR 4.0), presented with severe exacerbation (OR 6.1), and to have been treated at 1 particular center (OR 14.9). Forty-two (53%) of 90 hospitalized children were not given "intensive therapy." Children receiving "intensive therapy" were more likely to present with severe disease to EDs by using asthma guidelines (ORs 8.9, 3.0). Differences in the frequencies of all stabilization treatments were significant across centers. Magnesium is used infrequently in Canadian pediatric EDs in acute asthma requiring hospitalization. Many of these children also do not receive frequent albuterol and ipratropium, or early corticosteroids. Significant variability in the use of these interventions was detected.

Intravenous magnesium prevents atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials

BackgroundPostoperative atrial fibrillation (POAF) is the most common complication after coronary artery bypass grafting (CABG). The preventive effect of magnesium on POAF is not well known. This meta-analysis was undertaken to assess the efficacy of intravenous magnesium on the prevention of POAF after CABG.MethodsEligible studies were identified from electronic databases (Medline, Embase, and the Cochrane Library). The primary outcome measure was the incidence of POAF. The meta-analysis was performed with the fixed-effect model or random-effect model according to heterogeneity.ResultsSeven double-blind, placebo-controlled, randomized clinical trials met the inclusion criteria including 1,028 participants. The pooled results showed that intravenous magnesium reduced the incidence of POAF by 36% (RR 0.64; 95% confidence interval (CI) 0.50-0.83; P = 0.001; with no heterogeneity between trials (heterogeneity P = 0.8, I2 = 0%)).ConclusionsThis meta-analysis indicates that intravenous magnesium significantly reduces the incidence of POAF after CABG. This finding encourages the use of intravenous magnesium as an alternative to prevent POAF after CABG. But more high quality randomized clinical trials are still need to confirm the safety.

The Need for Large-Scale Randomized Evidence Without Undue Emphasis on Small Trials, Meta-analyses, or Subgroup Analyses

RANDOMIZED TRIALS OF ADEQUATE SIZE AND DURATION designed to test a priori hypotheses represent the most reliable design strategy to detect the most realistically small to moderate therapeutic effects of drugs. Such trials should achieve high adherence to an adequate dose of the drug and a sufficient number of clinical end points to distinguish reliably between the null hypothesis and the most plausible alternative hypothesis of small to moderate benefit or harm. With regard to the development of drugs to treat diabetes mellitus, the US Food and Drug Administration (FDA) has developed guidance for industry that somewhat overemphasizes results from meta-analyses of phase 2 trials that were not large enough to test realistic hypotheses about clinical cardiovascular (CV)events. Even inaggregate, suchresults should be considered more as hypothesis formulating than as hypothesis testing. The main need now is for trials that are large enough to have adequate statistical power. The quality and usefulness of any meta-analysis are dependent on the quality and comparability of data from the component trials. In particular, the trials combined should have high adherence and follow-up rates and should have reasonably comparable drugs, doses, and outcomes. The characteristics of the participants and the magnitude of effect from each trial must be sufficiently similar so that their combination will not produce a distorted estimate. Thus, metaanalyses can reduce the role of chance in the interpretation but may introduce bias and confounding. For example, a meta-analysis of rosiglitazone involved 42 randomized trials with a total of 26 011 patients who experienced 158 myocardial infarctions (MIs) and 61 deaths due to CV causes (CV death). The investigators concluded that rosiglitazone was associated with a significant increase in risk of MI (relative risk [RR],1.43; 95% confidence interval [CI], 1.03-1.98) as well as a nonsignificant increase in CV death (RR,1.64; 95% CI, 0.98-2.74). The chief value of this report should have been to formulate a hypothesis about one possible hazard of rosiglitazone that may offset any potential benefits. Furthermore, the widths of the CIs suggest that this meta-analysis was unable to distinguish reliably whether rosiglitazone conferred no hazard or a substantial hazard of CV events. Hypothesis formulation should lead to adequate hypothesis testing in another randomized trial of adequate size and duration designed a priori to address the question. The Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial was designed a priori to assess the noninferiority of rosiglitazone added to metformin or sulfonylurea compared with dual therapy metformin and sulfonylurea on reducing CV events among 4447 patients with type 2 diabetes. The primary prespecified outcome was time to first CV hospitalization or CV death with a hazard ratio (HR) noninferiority margin of 1.20, which is the upper bound of the 95% CI as recommended by the FDA. During a mean 5.5-year follow up, there were 321 incident primary clinical events in the rosiglitazone group and 323 in the active comparator group (HR, 0.99; 95% CI, 0.85-1.16), meeting the criterion for noninferiority. Thus, the results of the large-scale trial did not support the hypothesis formulated from the meta-analysis of smaller trials. Likewise, in a meta-analysis of 7 small trials evaluating use of intravenous magnesium during suspected acute MI, there were 25 deaths among 657 patients in the magnesium group vs 53 deaths among 644 patients in the placebo group (HR, 0.45; 95% CI, 0.15-0.74). Although the existing totality of evidence was compatible with the possibility that intravenous magnesium was an effective, safe, and inexpensive intervention, a prudent approach was to await the results of the large fourth International Study of Infarct Survival (ISIS-4) trial before routinely using this therapy. In ISIS-4, 58 050 patients with suspected MI were randomized to receive either intravenous magnesium or usual care. Patients treated with magnesium had a nonsignificant 6% increase in mortality, as well as significant increases in heart failure, death attributable to cardiogenic shock, and bradycardia. In subgroup analyses (which are useful to formulate but not test hypotheses) no significant differences were found among patients treated less than 6 hours after the onset of symptoms, those who received intravenous magnesium within 2 hours after thrombolytic therapy, and those who received neither thrombolytic therapy

Intravenous magnesium sulfate enhances the ability of dofetilide to successfully cardiovert atrial fibrillation or flutter: results of the Dofetilide and Intravenous Magnesium Evaluation

A previous study found that the adjunctive use of intravenous magnesium sulfate with ibutilide could increase the odds of a patient chemically cardioverting from atrial fibrillation (AF) or flutter (AFL) to normal sinus rhythm (NSR) by 78%. Whether or not intravenous magnesium has the same effect on dofetilide's ability to chemically cardiovert patients from AF/AFL to NSR is not known. This was a retrospective cohort evaluation of consecutive eligible patients receiving dofetilide for chemical cardioversion of AF or AFL at a single institution. All AF or AFL patients received dofetilide according to the institution's standard protocol, which required patients to remain as an inpatient for a minimum of 3 days or 6 doses after the initiation of dofetilide therapy. Patients receiving any dose of intravenous magnesium starting on the same day as dofetilide constituted the treatment group. Controls received dofetilide, but no intravenous magnesium any time prior to chemical cardioversion. Patients underwent continuous electrocardiographic monitoring throughout their hospital admission. Multivariable logistic regression analysis was used to determine the impact of intravenous magnesium on dofetilide's efficacy. A total of 160 patients in persistent AF or AFL (mean age 66.6 +/- 11.0 years, 70.0% male, 30.0% in AF or AFL >15 days, 54.4% hypertension, 37.5% heart failure, 16.3% valvular disease, 16.3% previous myocardial infarction, and baseline serum magnesium levels 2.1 +/- 0.26 mg/dL) and receiving dofetilide (mean dose 428 +/- 118 microg/dose) were included in this analysis. The overall chemical cardioversion rate with dofetilide irrespective of adjunctive intravenous magnesium utilization was 41.9%. The concurrent administration of intravenous magnesium (n = 50) was associated with a 107% increased odds of successful chemical cardioversion [adjusted odds ratio: 2.07 (95% confidence intervals: 1.00-4.33)] compared with those who did not receive magnesium (n = 110). Only one case of torsade de pointes occurred in the no magnesium group during the index hospital admission. Concurrent use of intravenous magnesium is associated with an enhanced ability of dofetilide to successfully convert AF or AFL.

Intravenous Magnesium Sulfate Enhances the Ability of Intravenous Ibutilide to Successfully Convert Atrial Fibrillation or Flutter

A previous randomized trial found that adjunctive use of intravenous magnesium (a total of 4 grams) can attenuate the corrected QT interval (QTc) prolongation associated with ibutilide, but its impact on ibutilide efficacy has not been elucidated. This was a cohort evaluation of 229 consecutive patients who received ibutilide in the presence or absence of intravenous magnesium. Multivariate logistic regression analysis was used to determine the impact of magnesium on ibutilide efficacy as well as the impact of magnesium dosing intensity on ibutilide efficacy. The overall chemical conversion rate with ibutilide in the presence or absence of magnesium was 59.8%. The concurrent administration of magnesium (n = 141) was associated with a 78% increased odds of successful chemical conversion (adjusted odds ratio, AOR; 1.78 [95% confidence intervals,CI 1.02-3.09]) compared to those who did not receive magnesium (n = 88). Magnesium dosing intensity appeared to be an important determinant of ibutilide efficacy, with the 4 grams dose associated with a threefold increase in the odds of successful chemical conversion (AOR; 2.98 [95% CI 1.46-6.11). The 1 to 3 grams subgroup was associated with only a trend toward an improvement. There was only one case of Torsade de Pointes (TdP) which occurred in the no adjunctive magnesium group. Concurrent use of magnesium enhanced the ability of ibutilide to successfully convert atrial fibrillation (AF) or flutter (AFl). The 4 grams magnesium dose appeared to provide the greatest benefit.

Use of intravenous magnesium to treat acute onset atrial fibrillation: a meta-analysis

Objectives:To assess the effects of intravenous magnesium on converting acute onset atrial fibrillation to sinus rhythm, reducing ventricular response and risk of bradycardia.Design and data sources:Randomised controlled trials evaluating intravenous...

Magnesium in the treatment of asthma

To provide an update of recent research on the role of magnesium in the management of asthma. Further evidence has been published that long-term oral magnesium supplementation does not lead to improved control in adult asthma. In contrast, updated meta-analyses of randomized controlled trials have confirmed the efficacy of both intravenous and inhaled (as an adjuvant to salbutamol nebulizer solution) magnesium therapy in severe asthma. This conclusion is still limited by the paucity of randomized controlled trials, however, with many issues yet to be firmly established, such as the efficacy in different patient subgroups, the dose regimes, and the optimal method of administration. International guidelines currently recommend the use of intravenous magnesium in severe asthma, and there is evidence that this approach is now widely used in emergency departments in North America. This audit also illustrated the emerging unregistered use of nebulized magnesium/salbutamol solution. Further investigation of the efficacy and safety of magnesium in severe asthma is now urgently required to determine its role in this clinical situation. The research community must heed the call for more research that is being made by funding agencies dealing with this area.

Does Nebulized Mg Add Benefit in Acute Severe Asthma

Treating acute severe asthma can be frustrating, as many patients do not respond to the standard combination of inhaled β-agonists, inhaled anticholinergics, and steroids. Studies of the use of intravenous magnesium in addition to standard treatment have had mixed results. …