Magnesium in veterinary clinical practice
MeSH keywords:cat, dog, magnesium
Magnesium (Mg2+) is an intracellular cation with a pivotal role in multiple vital functions. Its systemic importance is a common subject of research in medicine, although in companion animals, clinical and experimental data are still limited. Mg2+ homeostasis is achieved through absorption and reabsorption by the intestine and kidneys, respectively. Mg2+ disorders have been associated with prolonged hospitalisation and higher mortality rates, with neurological and cardiovascular clinical signs prevailing at presentation. Hypermagnesaemia is rarely diagnosed in clinical practice and is associated with impaired renal function or excessive Mg2+ administration, commonly manifesting as diminished to absent tendon reflexes and hypotension. In contrast, Mg2+ deficiency occurs more frequently in clinical practice and is associated with underlying comorbidities. Hypomagnesaemia with or without other concurrent electrolyte disorders, may result in systemic hypotension and cardiac arrhythmias due to a disruption in myocardial action potential (depolarisation and repolarisation phase). Mg2+ deficiency can also account for epileptic seizures or tetanic contractions.
Objective measuring and interpreting Mg2+ concentration are difficult because of its intracellular localisation, when blood serum Mg2+ measurements are the only tests available for clinicians. New techniques have been developed and used in experimental studies, but they are not yet available in the clinical setting. The beneficial properties of Mg2+ salts could be used in systemic diseases, but their administration is often avoided due to ambiguity of concentration measurements. Nevertheless, adverse effects can be avoided with careful administration of Mg2+ in underlying disorders in which the ion’s contribution could lead to more successful results.
Magnesium (Mg2+) is a cation with a central role in a wide range of vital functions in living organisms. In contrast to other ions like sodium (Na+), chloride (Cl-), calcium (Ca2+), and potassium (K+), research regarding Mg2+ disorders and their clinical significance in veterinary practice are limited. The main inhibiting factor for this is the inherent difficulty in measuring blood levels, considering that 99% of Mg2+ is intracellular. In recent decades, tests of measuring Mg2+ levels directly or indirectly have been developed. Studies in various fields of medicine have revealed its beneficial role, including intensive care treatment.
In human patients that required hospitalisation in intensive care units, 20% of them were found to have hypomagnesaemia and 9% hypermagnesaemia (Reinhart & Desbiens 1985). In another published report, the percentage of human patients with hypomagnesaemia reached 65% (Ryzenet al.1985). Whang has suggested measuring Mg2+ levels in human patient serum, in particular, when other electrolyte disorders co-exist, considering that measuring Mg2+ was found to be frequently omitted (Whang & Ryder 1990). More recent reports have associated the presence of hypomagnesaemia in human patients with severe Mg2+disorders with double the mortality rate, as compared with patients in which Mg2+ was within normal range. In intensive care hospitalised septic patients, acute kidney injury is often observed due to presumed abnormal microcirculation, glomerular filtration rate disruption and renal tubular epithelial cell dysfunction that often leads to Mg2+ disturbances (Meurer & Höcherl 2019).
Other experimental information in rats has been included in a 1957 study, in which Vitale et al. reported inhibition of oxidative phosphorylation in cardiac muscle cells of rats, due to Mg2+deficiency, indicating that Mg2+is important for energy production on a cellular level and ensures normal organ system function. Therefore, disorders of Mg2+ homeostasis may result in life-threatening conditions (Vitale et al. 1957). It can be deduced from studies both in people and experimental rats, that the significance of Mg2+ had been clear; therefore, studies in animals were conducted in order to confirm a similar significance.
In veterinary clinical practice, the first report was published in 1957, following the grazing of fresh green grass during the spring and autumn and the advent of hypomagnesaemic tetany, grass tetany or spring tetany in cattle (Kemp & Hart 1957). The presence of hypomagnesaemia is multifactorial and has not been completely understood. A main cause is low dietary Mg2+ uptake, as well as the presence of high dietary K+ levels that prevent Mg2+ absorption. In a research study performed in dogs that were admitted to intensive care unit, hypomagnesaemia was reported in 54% of cases, with the mortality rate being 2.6 times higher compared to dogs with normal Mg2+ levels in blood serum (Martin et al. 1994). A lower survival rate and prolonged duration of hospitalisation was also found in cats, when disruption of serum Mg2+ levels had developed (Toll et al. 2002). In a clinical study, serum Mg2+ abnormalities seem to be correlated with nephrolithiasis and chronic kidney disease in cats, in which hypermagnesaemia existed in 38.1% (16/42) and hypomagnesaemia in 14.3% (6/42) of cases (Chacar et al. 2019).
Mg2+disorders are mostly reflected in clinical signs of the metabolism, the cardiovascular and the central nervous system. Restoring Mg2+ levels to normal is recommended when such clinical signs are observed. Practical applications of Mg2+ supplementation, however, are not limited to such disorders, considering that they also contribute to anaesthesia, analgesia and treatment for tetanus.
The role of Mg2+
Mg2+ is important to mitochondria for ATP transport and energy production. It is involved in the metabolism of nucleic acids and many enzymes and contributes to the stability of phospholipid membranes. It can be found either as an intracellular (in bones, skeletal muscles, cardiac muscle cells) or an extracellular ion in the following three forms: the ionised or free form (biologically active), the protein bound form and the complex form. The main source of Mg2+ is dietary uptake; it is absorbed by the intestine where mechanisms of active and passive transport occur (Hayashi &Hoshi 1992). Furthermore, the role of kidneys in the excretion and reabsorption of Mg2+ is of particular importance, considering that normal renal function greatly affects the cation balance in the body (Quamme & Rouffignac 2000).
Intestinal absorption of Mg2+
Mg2+ absorption is accomplished through passive and active routes of transport, principally in the ileum and secondarily in the jejunum and colon (Hayashi & Hoshi 1992). The passive absorption is accomplished in three ways. Intestinal Mg2+ absorption depends on intracellular levels in epithelial cells and is affected by ionised form levels in the intestinal lumen. Furthermore, the reabsorption of water and salts results in the formation of positive charge in the intestinal lumen, the second factor that facilitates passive reabsorption of Mg2+ from the intestine (Kerstan & Quamme 2002). Finally, it is known that there are proteins in the tight junctions between epithelial cells, which function as ion channels, even though no information for their affinity towards Mg2+ is available (Kerstan & Quamme 2002).
According to studies in humans, active transport is accomplished through the effect of transport proteins on the membrane of intestinal epithelial cells (Bateman 2012). M proteins are a typical example of such proteins, and particularly TRPM6 and TRPM7, which combine ion channels with an intracellular protein kinase or enzymes. In this case, however, Mg-ATP (magnesium-adenosine-triphosphate) is the substrate of the enzyme portion of this channel; therefore, it can lead to inhibition of intracellular transport of Mg2+. This can occur when cells are replete in Mg2+, resulting in blocking of the passage of supplementary Mg2+ intracellularly through these channels (Bateman 2012).
Either passive or active, Mg2+ transport from the digestive tract is directly dependent on dietary uptake. High dietary content of Mg2+ facilitates passive transport, whereas, in case of the opposite, active transport predominates (Chubanov et al. 2005). In pathological conditions such as malabsorption disorders and chronic inflammatory bowel disease, hypomagnesaemia may develop.
Renal reabsorption of Mg2+
As it was mentioned above, kidneys contribute to Mg2+ homeostasis in the body. Eighty percent of the Mg2+ filtrated by the glomerulus enters the proximal tubule. In contrast to other cations, for which reabsorption can reach 60% in the proximal tubule, the percentage of Mg2+ is 10-15%. In this segment, reabsorption occurs through passive transport. At the ascending limb of the loop of Henle, 60-70% of the Mg2+filtered during glomerular filtration is reabsorbed (Quamme & Rouffignac 2000, Dai et al. 2001). The transport of sodium, chloride, and water from the intraluminal space to the intermediate renal tissue creates an osmotic gradient that causes Mg2+ to be reabsorbed through the tight junctions of epithelial cells (passive transport). Some of the hormones that increase Mg2+ absorption include parathormone, glucagon, insulin and aldosterone (Cole &Quamme 2000). In contrast, hypokalaemia, hypophosphatemia, and acidaemia have the opposite effect. Although the distal convoluted tubule does not have a role as significant as the ascending limb of the loop of Henle in Mg2+ transport, it regulates the excretion and final concentration of Mg2+ in urine. Reabsorption in this segment of the kidney occurs only through active routes which are similar to those aforementioned, located in the digestive tract. Therefore, in chronic renal failure there is a risk for hypermagnesaemia due to disruption in Mg2+ excretion in urine (Quamme & Rouffignac 2000, Dai et al. 2001).
Increased Mg2+ levels are uncommon in routine clinical practice, with the majority being iatrogenic or developing in patients with chronic renal failure (Zaman & Abreo 2003, Jackson & Drobatz 2004). The first published report on iatrogenic hypermagnesaemia in companion animals belongs to Jackson and Drobatz, describing two cases of hypermagnesaemia following intravenous infusion of the ion during treatment for hypomagnesaemia (Jackson & Drobatz 2004). In patients with underlying renal disease, iatrogenic administration of antacids, laxatives as well as enemas that frequently contain Mg2+ can lead to increased Mg2+ levels (Zaman & Abreo 2003, Swaminathan 2003).
In hypermagnesaemia, clinical signs affect the neuromuscular and cardiovascular systems (Table 1). Among the first clinical findings is the absence of tendon reflexes. Generalised muscle weakness or even flaccid paralysis can also develop, affecting the respiratory muscles and resulting in hypoventilation due to shallow breathing (Fassler et al. 1985). The effect of Mg2+ activity on neuromuscular synapses is countered by Ca+2, while signs of hypermagnesaemia are more severe in cases of hypocalcaemia (Swaminathan 2003).
High Mg2+ levels in the plasma can result in severe hypotension, since Mg2+ can cause peripheral vasodilation. It has been observed that both in humans and animal, values higher than 3-5 mEq L-1 have resulted in hypotension (Hoff et al. 1939).
In cases of Mg2+ administration, close monitoring of the cardiovascular system is recommended for potential electrocardiographic abnormalities and hypotension. If abnormalities are observed, administration should be stopped, and diuretics should be administered. In rare cases, Ca2+ gluconate is recommended in order to prevent the cardiotoxic effects of Mg2+ (Martin 1998, Bateman 2012, Bateman & Mathews 2017).
In an experimental research in 1999, Nakayama and associates studied the effect of iatrogenic administration of Mg2+ in dogs and concluded that doses between 0.1-0.2 mEq kg-1 do not cause haemodynamic disorders (Nakayama et al. 1999).
The effect of Mg2+ deficiency can involve multiple organ systems (Table2) and, as it was mentioned above, it is associated with prolonged hospitalisation and high mortality rates in dogs and cats (Martin et al. 1994, Toll et al. 2002). Diet poor in Mg2+ has been associated with delayed growth, skin lesions and peripheral oedemas (Bateman 2012, Bateman & Mathews 2017).
Clinical signs are readily observed in the clinical setting and usually stem from the cardiovascular and neuromuscular systems, as well as the reproductive and endocrine systems. Depending on the cause and severity of Mg2+ deficiency, these can vary from mild to life-threatening.
From a physiological perspective, cardiac muscle contraction is the result of a complicated mechanism, which is characterised by rapid exchange of intracellular and extracellular ions. In particular, a major contributing factor for this mechanism is the release of Ca2+ from the sarcoplasmic reticulum or its entry from the extracellular space. However, Ca2+ transport is closely associated with Mg2+ concentration (the intracellular as well as the extracellular ionised form), which happens to be a coenzyme of Ca2+ATPase. Ca2+ATPase is an enzyme responsible for Ca2+ transport back to the sarcoplasmic reticulum, when muscle contraction has been completed (Martin et al. 1994). Moreover, extracellular Mg2+ can act as a Ca2+ channel blocker preventing cytoplasmic overload (Iseri et al. 1983). Finally, Mg2+ is also a coenzyme of ion pumps, which transport Na+ and Ca2+ outside, and K+ inside the cardiac muscle cells (Martin et al. 1994).
Mg2+ deficiency is likely to lead to cardiac arrhythmias, such as atrial tachycardia, atrial fibrillation, supraventricular tachycardia and Torsades de Pointes (Iseri et al. 1992, Bateman 2012, Humphrey et al. 2014) due to disorders in the exchange between Ca2+ and Κ+ (depolarisation and repolarisation) in cardiac muscle cells. Normally, during the depolarization phase (phase 4), the intracellular Ca2+ is expelled through the Mg-ATPase and intracellular K+ which at this point is low and can be supplemented through the Mg-dependent Na+- and K+-ATPase. When Mg2+ deficiency develops, the above mechanism is not possible. Moreover, in cases of hypomagnesaemia, metadynamics can be caused due to intracellular Ca2+ concentrations. Such dynamics may also be caused by the occasional transport of Ca2+ through the sarcoplasmic reticulum. In cases of Mg2+ deficiency, impulse sites of extranodal origin are created combined with a reduction in K+, the transport of which is also delayed, resulting in recurring tachycardia (Iseri et al. 1983).
It is not possible to confirm whether the aforementioned arrhythmias are exclusively caused by Mg2+ deficiency, considering that hypokalaemia is often concomitant (Huang & Kuo 2007). In an experimental study in rodents that were fed diet lacking Mg2+, histopathological findings included inflammatory lesions in the myocardium were (Kramer et al. 2003). In addition, Mg2+ deficiency decreased the threshold for epinephrine-induced tachyarrhythmias in rats that had been administered inhalational anaesthesia(Crawford 2004). Consequences of abnormal levels of Mg2+ in the blood are also evident in the peripheral cardiovascular system. It is a fact that the presence of Mg2+ has a vasodilatory effect, considering that it affects the Ca2+ cycle in the peripheral vascular smooth muscle cells, resulting in vasoconstriction through this mechanism, which is negated by Mg2+, causing vasodilation. Therefore, in cases of Mg2+ deficiency, systemic hypertension is expected (Martin et al. 1994, Laurant & Touyz, 2000).
In dogs with perinatal eclampsia, hypomagnesaemia was found to be concomitant with hypocalcaemia. As a result, in cases of eclampsia, the supplementation of both ions should lead to more effective and faster remission of clinical signs (Aroch et al. 1999).
Research studies in humans indicate that in patients with diabetes mellitus (DM) hypomagnesaemia and insulin resistance may develop concurrently. It is considered that this is caused by increased renal excretion of Mg2+ through hyperglycaemic osmotic diuresis (Huerta et al. 2005). In a study in cats with uncomplicated DM and diabetic ketoacidosis (DKA), there was a distinct difference between the values of total magnesium (tMg) and ionised magnesium (iMg) in affected cats, compared to those in healthy control cats. In affected cats, lower values of both tMg and iMg levels were found. In hospitalised animal patients with DM and DKA, close monitoring is necessary for potential signs of hypomagnesaemia (Norris et al. 1999).
Regarding the central nervous and musculoskeletal system, hypomagnesaemia may lead to neuron overstimulation and increased neuromuscular transmission, usually clinically evident as epileptic seizures (Anderson et al. 1986). However, due to the fact that the sequelae of hypomagnesaemia are rarely clinically evident in companion animals, there is limited information available. Grass tetany in cattle caused by Mg2+ deficiency has been known for a long time (Kemp & Hart 1957). In such cases, low Mg2+ levels lead to increased acetylcholine release in neuromuscular junctions and, consequently, to the development of epileptic seizures and tetanic muscle contractions.
Mg2+ and other electrolytes
As expected after all the aforementioned data, disorders in Mg2+ homeostasis are likely to affect the homeostasis of other ions in the body as well. At this point, we will exclusively mention the mechanisms in which hypomagnesaemia may be the cause of K+ deficiency. This disorder originates from Mg2+ potential as a coenzyme of ATPase pumps. In this case, insufficient function of Na-K-ATPase and the Na-K-Cl transport system is the main reason for limited re-entry of K+ in cells and more extensive K+ losses (Whang et al. 1992, Dai et al. 2001). In Mg2+-dependent hypokalaemia, complications become worse, because the reabsorption of Mg2+ by the kidneys is reduced, due to lack of K+. During management of this situation, the administration of K+ alone is inefficient, unless Mg2+ levels are also restored. In clinical research studies in critically ill dogs, it was found that hypomagnesaemia co-existed with hypokalaemia (Khanna et al. 1998).
In dogs with hypoparathyroidism, there has been a correlation between parathormone (PTH), hypomagnesaemia and hypocalcaemia. Following administration of Mg2+, Ca2+ and PTH values were also restored (Bush et al. 2001). In Yorkshire Terriers, the co-existence of hypocalcaemia and hypomagnesaemia has been described in five cases of protein-losing enteropathy (Kimmel et al. 2000). Deficiency of these ions is attributed to intestinal losses, malabsorption, as well as vitamin D and PTH disorders. In animals with chronic enteropathies, neurological signs may develop due to the aforementioned electrolyte disorders, hence, restoring their levels is considered to be necessary (Bush et al. 2001).
Intracellular location of 99% of total Mg2+ impedes the process of accurate Mg2+ serum level assessment. Diagnostic testing methods are classified in two categories; the first is based on organ tissues enabling the measurement of total concentration of Mg2+, and the second is based on the regulation of Mg2+ level by the kidneys.
Selection of the most suitable tissue for the measurement of Mg2+ is a challenge and has been a subject of study for several researchers. Blood serum is preferred, considering that it is the transport medium for the cation, as it is easier to obtain and the most accessible tissue in clinical practice (Bateman 2012). In blood serum, tMg and iMg are measured, which comprise 1% and 0.2-0.3% of tMg in the body, respectively. Therefore, results are not always representative of the actual deficiency or excess of Mg2+. Examples are chronic cases of Mg2+ loss, in which Mg2+ stores are mobilised, causing tMg and iMg values to be within normal range, even though cation deficiency may still exist. In contrast, in acute cases of Mg2+ loss, it is possible to measure low levels in serum, even though there may be no deficiency (Woolddridge & Gregory 1999, Norris et al. 1999).
The diagnostic method that is based on renal Mg2+ regulation is limited in patients with renal dysfunction (Bateman 2012). In order to evaluate renal regulation of Mg2+, measuring of clearance and fractional excretion of Mg2+ in the urine, as well as the degree of total clearance in 24 hours are necessary. The absence of Mg2+ reference range in animals makes diagnostic methods that are based on urinary excretion measurements currently unreliable (Norris et al. 1999).
New methods of measuring Mg2+ levels, such as nuclear magnetic resonance spectroscopy and fluorescent intracellular probes emerge, offering more objective results, as they focus on measuring intracellular ion concentrations (Liu et al. 2018, Cameron et al. 2019). Both of the aforementioned methods have not yet been applied in clinical practice. For the moment, the interpretation of Mg2+levels in clinical cases should be combined with the evaluation of clinical signs and underlying comorbidities.
Indications of treatment with Mg2+ salts and practical applications
In veterinary clinical practice, dogs and cats with normal dietary habits are in no risk of developing this particular pathological condition, because approved dietary plans are rich in Mg2+. In contrast, patients with anorexia or cases with significant Mg2+ losses from the urinary or digestive tract are likely to develop hypomagnesaemia. Furthermore, multiple research studies, especially in human patients, have indicated that restoring of Mg2+ levels, as well as other electrolyte imbalances, leads to restoration of electrophysiological activity in patients with congestive heart failure and cardiac arrhythmias (Iseri et al. 1992, Bateman 2012).
In diabetes mellitus, even in cases of ketoacidosis, it appears that the restoration of Mg2+ homeostasis can play a supportive role in more efficient diabetic control (Norris et al. 1999, Huerta et al. 2005).
Indications regarding the therapeutic use of Mg2+ salts in bronchial asthma were first reported by Trendelenburg in 1912, who observed its bronchodilating effects in vitro. In human patients it appears to lessen the frequency and severity of asthma attacks. However, this has not yet been investigated in companion animals (Trendelenburg 1912, Bateman 2012, Humphrey et al. 2014).
In an experimental study in rats, Vink observed that after cerebral trauma, laboratory animals developed a reduction of intracellular Mg2+ in cerebral tissue. These animals were administered prophylactic treatment with magnesium sulfate and the Mg2+ levels remained high; they also had an improved survival rate (Vink et al. 1988).
Mg2+ salts have a wide safety margin (patients with renal disorders are an exception), therefore Mg2+ administration in the clinical setting should not be avoided due to lack of extensive studies. Mg2+ salts can be administered via various routes (Table 3). In emergency situations, it is possible to administer a high dose within a few minutes. Otherwise, the same dose can be infused in the first 24 hours and then over the next few days at a slower rate, until the Mg2+ dietary uptake can maintain Mg2+ levels within normal range. However, Mg2+ salt solutions with a content higher than 20% (200 mg ml-1) should be avoided. Mg2+ is compatible with dextrose 5%, with 0.9% saline solution and Lactated Ringer´s solution, as well as with gentamicin, cefazolin and metronidazole. In contrast, it has no physical compatibility with 10% fat emulsions, calcium gluconate, amphotericin, cefepime, ciprofloxacin, clindamycin, cyclosporine, dobutamine, hydrocortisone sodium phosphate, polymyxin, procaine, potassium phosphoric acid salt, and sodium phosphate (Bateman 2012, Humphrey et al. 2014, Bateman & Mathews 2017).
Administration of Mg2+ as adjunctive therapy in various clinical conditions
Tetanus can cause severe muscle contractions, occurring due to the inhibition of release of neurotransmitters, such as glycine and γ-aminobutyric acid. Magnesium sulphate has been supportively administered in dogs with generalised tetany, aiming in reducing tetanic muscle contractions and resulting in muscle relaxation, combined with muscle relaxants (Simmonds et al. 2011). During administration, it is recommended to monitor Mg2+ serum levels frequently and assess the patellar reflex because its reduction or absence might be an indication of hypermagnesaemia. Mg2+ seems to contribute to muscle relaxation, because it prevents Ca2+ entry in presynaptic terminals, resulting in the decrease of acetylcholine release and the reduction of presynaptic terminals sensitivity to the effect of acetylcholine (Simmonds et al. 2011, Fawcett & Irwin 2014).
Anaesthesia and analgesia
Mg2+ is reported to play a role in anaesthesia, by acting as an antagonist to N-methyl-D-aspartate (NMDA) receptors and Ca2+ channels (Sasaki et al. 2002). In an experimental model in rats, it was shown that an increase in Mg2+ levels decreased the required concentrations in inhaled anaesthetics (Thomson et al. 1988).
The potential mechanism underlying the effects of Mg2+ is based on blocking presynaptic Ca2+ channels in the hippocampus that regulate neurotransmitters of the central nervous system (Sasaki et al. 2002). Induction of anaesthesia through inhaled anaesthetics occurs by blocking these channels. As a result, their required concentration is reduced in cases when Mg2+ administration has preceded the inhaled anaesthetic administration, taking into account that part of these channels will be occupied (Sasaki et al. 2002).
In a clinical study, intravenous bolus infusion of Mg2+, followed by constant rate infusion, was found to reduce the amount of required halothane in dogs that were anaesthetised for ovariohysterectomy (Anagnostou et al. 2008).
The analgesic effect of Mg2+ has been studied both in human and animal patients after intravenous and intrathecal infusion (Bateman 2012). Despite the disagreement among researchers, Mg2+ seems to reduce sensitivity to pain through antagonising Ca2+ for the corresponding channels, the activation of NMDA receptors and the regulation of mediator release from presynaptic receptors (Iseri et al. 1983, Sasaki et al. 2002). Furthermore, Mg2+ prevents central sensitisation due to NMDA receptor inhibition in the dorsal horn, in cases of tissue trauma or inflammation (Adami et al. 2016). Nevertheless, currently Mg2+ is not recommended as an analgesic and, particularly, as a sole analgesic agent.
Mg2+ use seems to play a role in local anaesthesia as well. In a study, the combination of Mg2+ with ropivacaine in epidural anaesthesia in dogs that underwent tibial plateau levelling osteotomy reduced perioperative requirements of fentanyl (Adami et al. 2016). In an experimental study, Mg2+ contributed to a reduction in diabetic neuropathic pain in an experimental model in rats (Rondon et al. 2010).
Mg2+ is an electrolyte of primary importance for living organisms, because it plays a central role in a variety of vital functions, affecting all body systems, directly or indirectly. However, the lack of substantiated studies in companion animals poses an obstacle in understanding the significance of Mg2+ in veterinary clinical practice. The elucidation of matters such as the consequences of Mg2+ deficiency in companion animals, as well as the development of reliable methods for measuring Mg2+ levels, could alter the diagnosis and management of multiple pathological disorders. Despite the confusion surrounding the interpretation of Mg2+ measurement results, the combined evaluation of Mg2+ levels with cases developing clinical signs may contribute to a more effective solution.
Conflict of interest
The authors declare no conflicts of interest.
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