What's Magnesium Got To Do With It?

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This episode is based on:

Humphrey S, Kirby R, Rudloff E. Magnesium physiology and clinical therapy in veterinary critical care. J Vet Emerg Crit Care 2015. 25(2):210-225.

“Magnesium (Mg) is a cation with an escalating role in critical care medicine.”

Is this true?
If it is, is it a good thing?
Is the evidence base supporting this escalating role theoretical, experimental or clinical? 

Background theory

“magnesium plays a pivotal role in cellular energy production and cell-specific functions in every organ of the body. Excess or deficiency of this important cation can result in life-threatening complications.”

Majority (99%) intracellular, especially bone
Plasma magnesium: protein-bound, complexed (anions e.g. citrate, phosphate), ionised
Ionised Mg physiologically active form

Plasma [Mg] may not reflect cellular environment
Changes in plasma [Mg] may not reflect changes in total body [Mg]

Intracellular [Mg] maintained at 0.5–1 mmol/L despite significant fluctuations in extracellular [Mg].

Cellular functions:

“Magnesium plays a pivotal role in the electrophysiology and ion flux across cell and mitochondrial membranes” ultimately impacting on energy production and release.
Affects cellular functions via relationship with intracellular calcium; in general competes with or otherwise influences calcium movement.

Various other functions mentioned in article.

Total body magnesium content dependent upon intestinal and renal absorption and excretion

Measuring Magnesium

“Accurate measurement of total body magnesium is a challenge due to its intracellular location and activity. The current clinical standard is to quantitate serum total or ionized magnesium concentrations…Monitoring the biologically active serum ionized magnesium concentration is preferred over total serum magnesium concentration.”

Serum quantitation may not accurately reflect total body magnesium content – unresolved
Research methodologies that allow intracellular magnesium to be measured may become available for clinical use

Magnesium disorders

“Total body magnesium concentration is affected by dietary intake, gastrointestinal function, hormonal balance, redistribution of the magnesium cation, and excretion into a third body space or urine. Magnesium disorders can manifest with a multitude of clinical signs, none of which are specific for the magnesium disorder.”

Article includes summary of mechanisms, causes, clinical signs, and treatment recommendations for magnesium excess and deficiency.

*Patient may have clinical signs that are compatible with a magnesium disorder – but they will not be pathognomic for one
*Abnormal plasma [Mg] may support that signs are due to a magnesium disorder – but not necessarily
*Decision to treat: empirical; based on risk-benefit assessment

Magnesium excess

“The two most commonly reported causes of magnesium excess in both human and veterinary patients are renal failure and iatrogenic causes…Hypermagnesemia can occur when magnesium-containing drugs such as antacids, laxatives, or enemas are administered to patients with underlying renal disease….Hypotension is one of the key clinical complications of magnesium excess.”

[Martin LG, Matteson VL, Wingfield WE, et al. Abnormalities of Serum Magnesium in Critically III Dogs: Incidence and Implications. J Vet Emerg Crit Care 1994. 4(1):15-20]

  • Naturally occurring total hypermagnesaemia reported to occur in up to 13% of critically ill dogs admitted to the ICU of one teaching hospital
  • Found that dogs with hypermagnesaemia were 2.6 times more likely to die of their underlying disease than dogs with normal serum magnesium
  • Dogs with renal disease had the highest median values for serum magnesium 

Remember to critique the paper methodology yourself before attributing any significance to these reported results!

“The concept that naturally occurring hypermagnesaemia may have prognostic value warrants further study”
 
Magnesium deficiency

Total body magnesium deficiency can exist despite normal serum magnesium concentration.
“A diagnosis of ionized hypomagnesemia has been associated with a prolonged hospital stay in dogs…ileus in horses following colic surgery…as well as a prolonged hospital stay and a higher incidence of mortality in hospitalized cats…The hospital length of stay for critically ill dogs with hypomagnesemia was reported to be twice as long as those with normal serum magnesium….Hypomagnesemia was also associated with concurrent hyponatremia and hypokalemia in dogs.” Reference canine paper above, one equine paper and one feline paper.

“Hypomagnesemia is common in critically ill human patients”
“Although magnesium-depleted patients may represent a subset of patients with more severe disease, hypomagnesemia appears to be an independent predictor of outcome”. Reference one human study.
If there is good quality evidence that hypomagnesaemia is common in critically ill human patients, does the same apply to critically ill dogs, and what about critically ill cats?

Keep an evidence-based perspective to all this…..

  • Hypokalaemia can become refractory to standard potassium replacement therapy as a consequence of magnesium deficiency. Magnesium replacement may be necessary before potassium supplementation is effective.
  • Magnesium also apparently serves as a cofactor for insulin release and function, as well as in maintenance of appropriate cellular sensitivity to insulin. Insulin resistance may develop secondary to magnesium deficiency.
  • Diabetic ketoacidosis: “hypomagnesemia is a common finding in diabetic ketoacidotic people. Ketoaciduria and glucosuria promote urinary magnesium excretion, which can be exacerbated with fluid diuresis. In addition, significant cellular redistribution of magnesium occurs as it moves from the extracellular space to the intracellular compartment with insulin therapy. Close monitoring for clinical signs of a magnesium deficit is necessary since a total body deficit may not be reflected in the measured serum magnesium concentration.”
  • Calcium and magnesium are affected in a similar manner by hormones. As many as one-third of human patients with low serum magnesium may concurrently have low serum calcium. Correction of magnesium deficiencies may be required with refractory hypocalcaemia.
  • Magnesium deficiency has been shown to affect gastrointestinal function and motility.  Magnesium deficiency should be considered a differential in any patient with decreased stomach or intestinal motility.
  • “Magnesium has been successfully used in the treatment of preeclampsia and eclampsia in women since 1912…The anticonvulsant of choice for treating seizures due to eclampsia is magnesium…Hypomagnesemia may also be a factor in dogs presenting with eclampsia and should be considered when managing dogs with signs of eclampsia.”
  • "Cardiac conduction abnormalities are one of the most common and serious manifestations of magnesium deficiency. Cardiac arrhythmias associated with hypomagnesemia include ventricular tachycardia, ventricular fibrillation, supraventricular tachycardia, atrial fibrillation, digitalis toxicity associated arrhythmias, and torsades de pointes (TdP).” But the authors point out that “Magnesium's role in the pathogenesis of arrhythmias is difficult to ascertain since magnesium deficits often coexist with potassium and calcium deficiencies….Multiple studies in both human and veterinary patients have documented resolution of TdP after magnesium sulfate infusion… Magnesium supplementation decreases the incidence of ventricular arrhythmias and atrial fibrillation following cardiopulmonary bypass and coronary artery bypass in humans with magnesium deficiency.” Some human medics use magnesium in the treatment of ventricular dysrhythmias.

Treatment of magnesium disorders

“The decision to treat a suspected or diagnosed magnesium disorder will depend on the severity of the clinical signs and the magnitude of change from normal range of the serum magnesium level of the patient.”
Provide some more detailed treatment recommendations with mostly human medicine references

Magnesium excess

Hypermagnesaemia treated by replacing magnesium-containing medications or fluids with magnesium-free ones.
Promoting urinary excretion and inhibiting renal tubular reabsorption of magnesium are mainstays of treatment for moderate to severe hypermagnesaemia and when clinical signs are apparent (e.g. cardiac arrhythmia, hypotension). Use IV sodium chloride +/- diuretics.
Acute magnesium toxicity from iatrogenic overdose treated with additional calcium gluconate
“Hemo- or peritoneal dialysis using magnesium-free dialysate may be necessary to treat symptomatic magnesium excess resulting from kidney disease or iatrogenic overdose.” 

Magnesium deficiency

“If the magnesium deficit is mild, dietary changes and oral magnesium salts such as magnesium carbonate or oxide may be sufficient to increase magnesium intake….Oral magnesium supplementation…should be considered in small animal patients at risk for chronic mild magnesium deficit, for example, those with GI malabsorptive diseases or chronic digoxin or loop diuretic therapy.”

“Animals symptomatic for low magnesium should be treated with an IV infusion of magnesium sulfate or magnesium chloride” and they recommend accounting for the magnesium content of any IV fluids being used when calculating magnesium supplementation doses.”

“the optimum dosage and rate of magnesium administration has not been defined for veterinary patients”

Reportedly a single experimental canine study has been the basis of the magnesium sulfate dose recommendation in dogs and cats.

Magnesium Infusion as an Adjunct to Therapy

“The multifaceted role of magnesium in cells has led researchers and clinicians in human medicine to explore the effects of infusing magnesium as an adjunct to therapy for various conditions.”
Cite a reference from 1974 for potential use in shock resuscitation
“Current studies of brain injury, spinal injury, pain, sepsis and systemic inflammatory response syndrome, hypercoagulable states, eclampsia, tetanus, and ischemia have demonstrated potential beneficial effects from magnesium administration. In these situations, magnesium administration is not given to replace a documented magnesium deficiency but instead given for its beneficial effects in specific cells. Though all syndromes reported in people may not be common in veterinary patients, knowledge of the possible mechanisms of action of magnesium infusion on various tissues may allow extrapolation into the veterinary population of patients.”

The authors say that current studies have demonstrated potential beneficial effects in a variety of scenarios. We should explore the evidence for that statement further to ensure that we are happy that it is legitimate.
And, is extrapolating from humans to veterinary patients a legitimate practice?

“Magnesium sulfate has been utilized in the treatment of autonomic dysfunction associated with severe generalized tetanus in both people and dogs.” Reference a single case report from JVECC in 2011. Much greater anecdotal experience exists but to date use of magnesium in tetanus remains inconclusive.

Risk-benefit assessment:

“The administration of magnesium as an adjunctive therapy in the tetanus patient has not been associated with adverse side effects” – may not help but unlikely to do any harm so maybe give it a go?
Potential to actually induce hypermagnesaemia

Conclusions:

  • “Magnesium is an important intracellular cation required for energy production and cell function in every organ.
  • Changes in magnesium homeostasis have consistently been correlated with increases in morbidity and mortality in veterinary and human critical patients.
  • Assessment of serum magnesium concentration should become a routine part of critical patient evaluation since the clinical signs and conditions associated with magnesium disorders can be nonspecific and varied.
  • Equipment to measure serum ionized or total magnesium is readily available in-hospital.
  • However, measurement of serum magnesium may not reflect total body magnesium concentration.
  • The serum magnesium concentration combined with clinical signs and conditions associated with magnesium disorders are used to make the diagnosis and to monitor treatment.
  • Research is exploring the role of magnesium infusions as an adjunct to standard therapy for clinical disorders such as head trauma, reperfusion injury, and vascular disease.
  • Future studies are expected to better define the role of magnesium in critical illness and investigate potential benefits of magnesium infusion in veterinary patients.”

SJ: “I guess my position is that when it comes to the clinical aspects and recommendations that the authors make, I don’t necessarily disagree, however I am also not sure that there is the evidence base in dogs and cats to support the statements at this time. So for me it is most definitely an area of on-going interest to see what more comes to light going forward.”

Please do get in touch if you have any comments or questions using the contact form, via email at shailenjasani@gmail.com, via Twitter @VetEmCC or via Facebook at the Veterinary ECC Small Talk page.

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