EAL

HF: Magnesium (2007)

Citation:

Study Design:

Class:

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Quality Rating:

Research Purpose:

The purpose of the study was to evaluate the acute effect of intravenous magnesium chloride on the frequency and severity of ventricular arrhythmias in 30 patients with symptomatic heart failure.

Inclusion Criteria:

Age 18 or older
Left ventricular ejection fraction of 40%
Presence of heart failure for at least one month
New York Heart Association Class II to IV
Normal sinus rhythm.

Exclusion Criteria:

History of symptomatic ventricular ectopy
Antiarrhythmic drug therapy
Calcium channel antagonists
Beta-blockers
PR interval over 0.2 seconds or a serum creatinine above two mg per dL.

Description of Study Protocol:

Recruitment: Study subjects were recruited prospectively by review of patients seen by the Heart Failure Program at the University of North Carolina at Chapel Hill
Design: Subjects were hospitalized for four days in the Clinical Research Center. The sequence was baseline-magnesium-washout-placebo or baseline-placebo-(Day Three)-magnesium.
Blinding used: Double-blind.

Intervention

After determination of blood chemistries, the patient was given a bolus dose of magnesium chloride (0.3mEq per kg) in 5% dextrose in water or placebo (D5W alone) over 10 minutes, followed by a continuous infusion of magnesim chloride (0.08mEq per kg per hour) or placebo for 24 hours
Day Three was a washout day for those given magnesium on Day Two
On Day Four, the protocol was the same as on Day Two, except the alternate therapy was given to complete the crossover design.

Statistical Analysis

The study sample size of 30 was estimated to have an 80% power to detect a target difference of 50% in arrhythmia frequency between magnesium and placebo days
The Wilcoxon signed-rank test was used for statistical comparison of the frequency of ventricular arrhythmia and the fastest rate and longest duration of episodes of ventricular tachycardia between monitoring periods
The possibility of a carryover effect was analyzed in two ways: The differences between the average ventricular ectopy over two treatment periods (magnesium and placebo) and baseline data for both sequences were compared; additionally, the differences between ventricular ectopy on washout and baseline days were compared for each sequence.
Blood pressure, heart rate and electrolyte levels during magnesium and placebo infusion were compared by paired student's T-tests.

Data Collection Summary:

Timing of Measurements

Blood pressure and heart rate were recorded at baseline and at two, four, six, eight, 10, 15, 20 and 30 minutes and at one, 1.5, two, three, five, seven, 12 and 24 hours
Serum magnesium concentrations were determined at baseline, at the end of the bolus (10 minutes) and at the following intervals: 15, 20 and 30 minutes and one, 1.5, two, three, five, seven, 12 and 24 hours
On Day Three (washout day for the subjects who received magnesium on Day Two), a blood sample for electrolytes was taken and Holter monitoring was continued
On Day Four, the protocol was the same as on Day Two, except the alternate therapy was given
On Day Five, the subject had a final blood sample taken and was discharged
All patients were monitored by telemetry and Holter throughout the study.

Dependent Variables

Variable One: Ventricular ectopy, measured by Holter monitor as premature ventricular contractions (PVC)
Variable Two: Couplets per day
Variable Three: Ventricular tachycardia, measured by Holter monitor
Variable Four: Serum magnesium by blood test.

Independent Variables

Variable One: Magnesium chloride (0.3 mEq per kg) in 5% dextrose in water or placebo (D5W alone) over 10 minutes, followed by a continuous infusion of magnesim chloride (0.08 mEq per kg per hour).

Control Variables

D5W.

Description of Actual Data Sample:

Initial N

35.

Attrition (Final N)

30 (21 men and nine women)
Patients were excluded because of incomplete Holter monitor monitoring
Heart failure exacerbation before randomization
One patient developed hypoglycemia.

Age

49±9.6 years.

Ethnicity

Not noted.

Other Relevant Demographics

70% were NYHA class II and 30% class III
Left ventricular ejection fraction was significantly depressed at 23±8%
All patients were receiving an angiotensin-converting enzyme inhibitor and digoxin, 97% were receiving diuretic agents
Potassium supplementation was being given in 48% (14 of 29) of patients on diuretics
Other cardiac medications included nitrates and clinidine in three subjects each
Magnesium supplementation was discontinued in two patients before study entry
Mean baseline serum magnesium concentration was 2.0±0.1 mg per dL (wnl)
Only two of the subjects in this study were hypomagnesemic (=1.5 mg per dL) prior to treatment.

Location

North Carolina.

Summary of Results:

Variable	Magnesium	Placebo	Statistical Significance
Ventricular Ectopy (PVCs per Hour)	70±26	149±64	P<0.001
Couplets per Day	23±11	94±59	P=0.007
Episodes of V-tach per Day	0.8±0.2	2.6±1.0	P=0.051
Baseline Serum Magnesium	2.0±0.1	2.2±0.1	P=0.037
Serum Magnesium (mg per dL)	4.2±0.1	Not listed	P<0.001

Other Findings

Intravenous infusion of magnesium chloride did not affect systolic or diastolic blood pressure
Heart rate transiently increased by 9% during the magnesium bolus, compared with placebo
After the bolus, there was no difference in heart rate between magnesium and placebo days over the following 24 hours.

Adverse Effects

Transient flushing (N=12), burning at the intravenous site (N=3) and transient paresthesia (N=1) occurred during infusion of the magnesium bolus
No serious adverse effects occurred.

Author Conclusion:

This study demonstrated that acute parenteral administration of magnesium chloride, in a dose that augments the serum concentration two-fold, results in a significant reduction in ventricular arrhythmia in patients with symptomatic heart failure
Further investigation of the dose-response relationship and the effect of chronic oral magnesium administration on ventricular arrhythmia, in a larger population of patients with congestive heart failure, is warranted.

Limitations

Whether similar beneficial effects on ventricular arrhythmia would occur during chronic oral administration of magnesium, independent of an effect on serum potassium, is unknown
Additional studies of larger numbers of patients will be required.

Funding Source:

University/Hospital:

University of North Carolina at Chapel Hill

Reviewer Comments:

Only two of the subjects in this study were hypomagnesemic prior to treatment. Serum magnesium is a poor indicator of body stores. Therefore, it is difficult to say who would benefit from this therapy, e.g., should all patients with HF and arrhythmias be treated with magnesium regardless of their magnesium status or is there a way to identify those who might benefit from this therapy?
The reduction in arrhythmias seen with magnesium infusion disappeared when it was discontinued. The author notes that the results of oral magnesium supplementation have been mixed, with the effect perhaps dose-related. More research is needed, using larger sample sizes and oral dosage in order to determine the clinical significance of the findings in this study.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		???
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	Yes
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	???
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	Yes
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	No
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	Yes
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes