Summary Of Evidence

Schelling JR (1999) reported a case study of severe symptomatic hypermagnesemia that resulted from excess exogenous magnesium intake in a patient with renal failure. In conclusion, this report highlights that symptomatic hypermagnesemia is often iatrogenic, and caution should be used before prescribing magnesium containing medications in the context of acute renal failure.⁴

Tong GM (2005) reviewed magnesium deficiency in critical illness by discussing its causes and its clinical implications based on the available clinical trials. The use of magnesium therapy is supported by clinical trials in the treatment of symptomatic hypomagnesemia and preeclampsia and is recommended for torsades de pointes.⁵

Khan (2013) studied 3530 participants from the Framingham Offspring Study and were free of atrial fibrillation (AF) and cardiovascular disease (CVD). They used Cox proportional hazard regression analysis to examine the association between serum magnesium at baseline and risk of incident AF. They concluded that low serum magnesium was associated with the development of AF in a longitudinal, community-based cohort over 20 years of follow up. They found that those in the lowest quartile of serum magnesium were approximately 30% more likely to develop AF than those in the upper 3 quartiles. Although previous studies have reported an association between low serum magnesium and AF in the context of cardiac surgery, the present study was the first to demonstrate this association in the broader community.⁶

Kieboom (2016) studied the association of serum magnesium levels with both coronary heart disease (CHD) and sudden cardiac death (SCD) within the Rotterdam Study, a prospective population-based cohort study among middle-aged and elderly persons with adjudicated end points and long term follow up. In this prospective population-based cohort study among 9820 participants with a median follow-up of 8.7 years, they found that low serum magnesium was associated with an increased risk of CHD mortality and SCD. When they excluded SCD from the CHD mortality end point, they found that higher serum magnesium levels were associated with a lower risk of non-sudden CHD mortality.⁷

Rooney (2020) using data from over 2000 older adult participants of the Atherosclerosis Risk in Communities (ARIC) Study, characterized cross-sectional associations of serum magnesium concentrations across the spectrum of AF burden and other arrhythmias based on up to 2 weeks of continuous electrocardiogram (ECG/EKG) recording. The multi-center prospective ARIC Study began in 1987-1989. Visit 6 occurred in 2016-2017. They concluded that low serum magnesium was associated with greater premature ventricular contractions (PVCs) burden as measured over 2 weeks of ECG/EKG monitoring. The limitations to the study are, as this analysis was cross sectional, the temporality of the association cannot be established particularly considering the complexity of magnesium homeostasis and cardiac electrophysiology. Residual confounding is another possibility given the observational nature of the study. It is plausible that those with arrhythmias are sicker and have other confounding characteristics shared by those with low circulating magnesium. The major strengths of this study were the community-based population and rigorous characterization of arrhythmia burden using a novel ECG/EKG monitor worn for up to 2 weeks.⁸

Del Gobbo (2013) performed a systemic review and meta-analysis examining the association of circulating and dietary magnesium with incidence of CVD, ischemic heart disease (IHD) and fatal IHD. They concluded that circulating magnesium was significantly associated with a lower risk of CVD, with trends toward a lower risk of IHD and fatal IHD. Dietary management was associated with a significantly lower risk of IHD and showed a nonlinear association with fatal IHD. Their findings support the importance of dietary recommendations to increase magnesium rich foods. The strengths were their data derived from a systematic search and meta-analysis of prospective studies which provided the best available evidence of how circulating and dietary magnesium may influence CVD risk. The limitation of their findings was constrained availability of published or unpublished data on magnesium-CVD associations.⁹

Analysis of Evidence

The analysis of evidence reviewed for magnesium included a systemic review and meta-analysis, multi-center prospective study, prospective population-based cohort study, longitudinal community-based cohort and a case study. The literature supports that low serum magnesium levels is associated with an increased risk of CHD mortality and SCD.

The literature reviewed concluded that low serum magnesium was associated with the development of AF. The literature supports that low serum magnesium was associated with greater PVC burden. The literature reviewed reported on a case study that highlighted symptomatic hypermagnesemia resulting from excess exogenous magnesium intake in the context of renal failure.

Magnesium is an essential ion in the human body, playing an important role in practically every major metabolic and biochemical process, supporting and maintaining cellular processes critical for human life. Magnesium plays an important physiological role, particularly in the brain, heart, and skeletal muscles. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Intracellular magnesium stores are found in high concentration in mitochondria, where this element plays a pivotal role in the synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate.¹

Measurement of magnesium levels is used as an index to (1) metabolic activity in the body such as, carbohydrate metabolism, protein synthesis, nucleic acid synthesis, contraction of muscular tissue and (2) renal function, because 95% of magnesium is filtered through the glomerulus is reabsorbed in the tubules.²

Covered Indications

Magnesium testing is considered reasonable and necessary under the following conditions:

1. Hypomagnesemia which can be induced by 2 major mechanisms: gastrointestinal or renal losses. Symptoms of low magnesium include: weakness, muscle cramps, confusion, irregular heartbeat, seizures.

Conditions which can produce hypomagnesemia include but are not limited to the following²:

• • • cardiac arrhythmias
    • proton pump inhibitors
    • alcohol
    • uncontrolled diabetes mellitus
    • hypercalcemia
    • posttransplant patients
    • other acquired tubular dysfunction
    • malabsorption syndromes
    • familial renal magnesium wasting
    • volume expansion
    • aminoglycoside antibiotics nephrotoxicity
    • amphotericin B nephrotoxicity
    • cisplatin
    • pentamidine
    • calcineurin inhibitors
    • digoxin
    • malabsorption syndromes
    • parenteral alimentation with inadequate magnesium content
    • diarrhea
    • diabetic ketoacidosis
    • diuretic therapy
    • hyperaldosteronism
    • hypoparathyroidism
    • hyperthyroidism
    • prolonged intravenous (IV) therapy
    • prolonged nasogastric suction
    • antibodies targeting the epidermal growth factor (EGF) receptor

2. Hypermagnesemia which can be induced in 2 settings: when kidney function is impaired and /or when a large magnesium load is given, whether intravenously, orally, or as an enema. Symptoms of high magnesium include: muscle weakness, fatigue, nausea and vomiting, trouble breathing, cardiac arrest.

Conditions which can produce hypermagnesemia include but are not limited to the following²:

• • • kidney impairment
    • magnesium infusion
    • oral magnesium ingestion
    • magnesium enemas
    • familial hypocalciuric hypercalcemia
    • hypercatabolic states, such as tumor lysis syndrome
    • diabetic ketoacidosis
    • lithium ingestion
    • milk alkali syndrome
    • adrenal insufficiency
    • rhabdomyolysis

Limitations

Services that are not reasonable and necessary cannot be covered by Medicare as published in CMS Internet-Only Manual, Pub. 100-08, Medicare Program Integrity Manual, Chapter 13, §13.5.4 Reasonable and Necessary Provision in an LCD and under Title XVIII of the Social Security Act §1862(a)(1)(A).