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Ann Thorac Surg 1997;64:572-577
© 1997 The Society of Thoracic Surgeons

Current Review

Magnesium Deficiency and Cardiogenic Shock After Cardiopulmonary Bypass

Waldemar Storm, MD, Jerry J. Zimmerman, MD, PhD

Pediatric Intensive Care, MeritCare Children's Hospital, Fargo, North Dakota, and Pediatric Critical Care Fellowship and Research Programs, University of Wisconsin-Madison Medical School, Madison, Wisconsin


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Case Report
 Comment
 References
 
Magnesium is an important cation that has a key role in cellular processes of energy transfer and utilization involving adenosine triphosphate, and influences cell membrane functions. Its antiarrhythmic properties are well-known and it is widely recognized as an adjunct for the treatment of arrhythmias after myocardial infarction and cardiopulmonary bypass. Magnesium may influence hemodynamic performance through its effects on vascular tone, modulation of intracellular calcium, regulation of catecholamine activity, and its essential role in adenosine triphosphate metabolism. The potential for magnesium deficiency to affect cardiovascular performance may be especially relevant in ischemic states. We report a case of cardiogenic shock developing after cardiopulmonary bypass that was initially unresponsive to therapeutic intervention, but that resolved promptly after magnesium administration. The potential role of magnesium in enhancing hemodynamic performance is discussed, with a review of its cellular metabolic properties and activities.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Case Report
 Comment
 References
 
Magnesium, the fourth most common cation and second most common intracellular cation in the body [1, 2], is required for numerous metabolic processes essential for life. All enzymatic reactions involving adenosine triphosphate (ATP) require magnesium (Mg), which combines with ATP to form the true substrate molecule, Mg-ATP [3]. By destabilizing the terminal phosphate bond of ATP, Mg may facilitate transfer of phosphate [3] (Fig 1Go). Thus Mg is involved in cellular processes of energy transfer and utilization [3–5] (Fig 2Go). Magnesium plays a key role in cell membrane functions, neuromuscular transmission, cardiac muscle excitability, and vascular tone [6]. Magnesium exerts both antiarrhythmic and hemodynamic effects on the cardiovascular system. The antiarrhythmic effects have been extensively investigated [5, 7] and appear to be related to magnesium's properties of calcium-channel blocking, activation of ATP, and regulation of intracellular potassium [5]. Magnesium is widely advocated in the treatment and prophylaxis of arrhythmias, particularly in acute myocardial infarction [8], after cardiopulmonary bypass (CPB) [9], and in digitalis toxicity [7, 10].



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  		Fig 1. . Structure of adenosine triphosphate complexed with Mg2+. Magnesium may facilitate energy transfer by destabilizing the energy-rich terminal phosphate bonds of adenosine triphosphate.

 


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  		Fig 2. . Adenosine triphosphate (ATP) is the key link between energy-producing and energy-consuming cellular functions, whereas other nucleoside triphosphates are involved in transferring energy. (ADP = adenosine diphosphate).

 
Magnesium infusion causes vasodilation and reduced vascular resistance, but its hemodynamic effects may be more complex than generally recognized. Cardiopulmonary bypass and other ischemic events that are common in critical illness often result in depletion of cellular magnesium [4, 9, 11]. We report a case of postoperative cardiogenic shock in a child that appeared to result from alterations in Mg homeostasis and to respond to Mg infusion with marked hemodynamic improvement.


   Case Report
Top
 Footnotes
 Abstract
 Introduction
 Case Report
Comment
 References
 
A 31/2-year-old boy had undergone repair of congenital Tetralogy of Fallot cardiac defects at 2 years of age. He later developed chronic heart failure with dyspnea and poor exercise tolerance. Cardiac catheterization 16 months after the original repair demonstrated residual atrial and ventricular septal defects with bidirectional shunt, pulmonic valve insufficiency, and severe tricuspid valve regurgitation. Medical management had included digoxin, furosemide, enalapril, and potassium supplementation. The patient was malnourished and cyanotic. After a period of inpatient care to optimize nutrition and medical management, he underwent surgical repair of the residual cardiac defects under high-dose fentanyl anesthesia and circulatory arrest. Cardiopulmonary bypass time was 4 hours, with aortic cross-clamp time of 85 minutes. Blood product replacement (packed red blood cells, fresh-frozen plasma, platelets, albumin) was approximately 2,000 mL. Postoperatively a slow junctional cardiac rhythm of 70 to 80 beats/min developed in the patient and required atrioventricular sequential pacing. He received morphine sedation and inotropic support with dopamine at 3 µg · kg-1 · min-1, CaCl2 at 2.5 mg · kg-1 · h-1, and epinephrine at 0.06 µg · kg-1 · min-1. He was hemodynamically stable. Serum electrolytes, arterial blood gases, and hematocrit were normal. Urine output was approximately 3 mL · kg-1 · h-1. Chest roentgenogram demonstrated stable cardiomegaly and reduction of previous chronic pulmonary vascular congestion.

On the morning of the third postoperative day the junctional rhythm persisted, and pacing was continued at 130 beats/min, along with inotropic and ventilator support. Blood pressure was 75 to 80 mm Hg systolic over 40 to 50 mm Hg diastolic, central venous pressure was 24 mm Hg, and left atrial pressure was 16 mm Hg. Digoxin was resumed at 8 µg · kg-1 · day-1 intravenously. Laboratory data at this time included the following values: sodium, 126 meq/L; potassium, 5.1 meq/L; ionized calcium, 4.95 meq/L; phosphorous, 3.6 meq/L; magnesium, 1.8 meq/L; albumin, 3.0 mg/dL; lactic acid, 1.7 meq/L; hematocrit, 40%; pH, 7.44; arterial carbon dioxide tension, 40 mm Hg; arterial oxygen tension, 106 mm Hg; HCO3-, 26.4 meq/L. On the afternoon of the same day there were signs of circulatory failure, and cardiogenic shock developed over a period of 1 to 2 hours. There was no evidence of bleeding. Hematocrit and serum chemistries remained unchanged. An echocardiogram demonstrated extremely poor left ventricular contractility. Dopamine was increased to 20 µg · kg-1 · min-1, dobutamine added at 20 µg · kg-1 · min-1, and epinephrine increased to as high as 4 µg · kg-1 · min-1. Volume infusion, milrinone infusion, and bolus injections of CaCl2 were given, all with no benefit. Bolus injections of epinephrine (10 µg/kg) were required to maintain systolic blood pressure greater than 50 mm Hg. The possibility of adrenocortical insufficiency was considered and methylprednisolone (10 mg/kg) was empirically given. Blood cultures were obtained and broad-spectrum antibiotic therapy initiated. Preparations were begun to provide extracorporeal life support.

A single bolus injection of 250 mg of magnesium sulfate (25 mg/kg) was given for approximately 10 minutes and simultaneously there was an immediate rise in the monitored arterial blood pressure from 45 mm Hg systolic over 20 mm Hg diastolic to 150 mm Hg systolic over 80 mm Hg diastolic. The epinephrine infusion was decreased to 1 µg · kg-1 · min-1, and after 30 minutes the hypertensive response was sustained. Infusion rates of epinephrine, dopamine, and dobutamine were rapidly decreased. Peripheral perfusion was excellent. The echocardiogram now showed dramatically improved left ventricular contractility. Arterial O2 saturation was 95%. Digoxin was discontinued. Methylprednisolone at 8 mg · kg-1 · day-1 was continued, and scheduled doses of magnesium sulfate (250 mg every 4 hours) were given for 24 h and then as required to maintain serum magnesium level of 2.0 to 2.5 meq/L. Parenteral nutrition was provided.

Two days later epinephrine had been discontinued. There was no further evidence of cardiogenic shock. Serum magnesium remained between 1.9 and 2.5 meq/L, ionized calcium was 4.97 meq/L, and potassium was 5.2 meq/L. Blood cultures obtained on day 3 were eventually positive for Streptococcus viridans. The patient was extubated on day 10. Slow junctional rhythm persisted, and atrioventricular sequential pacing remained necessary for adequate cardiac output. Eventually implantation of a permanent cardiac pacemaker was required.


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Case Report
 Comment
References
 
Severe cardiogenic shock developed in this child during the late postoperative period after a cardiac operation and CPB. He failed to respond to multiple inotropic agents, and only when magnesium sulfate was administered was there a sudden and sustained improvement. Because there had been multiple interventions during the 2 hours before injection of MgSO4, it cannot be ascertained that this intervention alone reversed the cardiogenic failure. Undoubtedly multiple factors may have been involved. However, his caregivers were impressed that the association between administration of MgSO4 and clinical improvement was direct, immediate, and dramatic.

The potential influence of Mg on hemodynamic function has perhaps been less well appreciated than its antiarrhythmic properties. Magnesium infusion has variously been reported to cause either negative [12] or positive [13] inotropic effects. Enhanced production and release by vascular smooth muscle of the potent vasodilator prostacyclin [14, 15], inhibition of cellular calcium entry [16], and regulation of endothelial-derived relaxing factor production or release [17] may be the mechanisms by which Mg causes vasodilation with a resultant decrease in systemic vascular resistance [18], pulmonary vascular resistance [19], and coronary artery resistance [20]. Rasmussen and associates [19] noted a reduction in mean arterial pressure and pulmonary artery pressure associated with decreased systemic vascular resistance and pulmonary vascular resistance after Mg infusion in patients with chronic ischemic heart disease and congestive heart failure. Mroczek and coworkers [18] administered MgSO4 to hypertensive and normotensive adult human subjects and documented a similar increase in cardiac index (mean, 33%) and stroke volume index (mean, 21%) in both groups. Systemic vascular resistance was decreased slightly more in the hypertensive group. James and colleagues [13] measured hemodynamic responses to Mg infusion in an adult baboon model. Increasing serum Mg levels correlated with decreased systemic vascular resistance and increased cardiac output, stroke volume, and stroke work. Increased cardiac output largely compensated for decreased systemic vascular resistance, with little decrease in systemic blood pressure at Mg levels less than 5 mmol/L (10 meq/L).

Magnesium is primarily an intracellular cation. About 50% to 60% of total body Mg content resides in the skeleton, another 20% in muscle. Extracellular fluid Mg, less than 1% of the total body content [1, 21], exists as free ion (55%), protein bound (30%), and complexed with other ions (15%) [22, 23]. Total serum measurements do not accurately reflect intracellular Mg status [5, 6]. Serum Mg may be normal, as in our patient, despite clinically significant depletion of intracellular content [6]. Intracellular Mg may be released from binding sites with cellular injury and death [24], and hypermagnesemia may be a marker of serious tissue damage and hypoperfusion states [25]. Magnesium efflux will result in increased urinary Mg loss, which may be exacerbated even more by the lowered renal excretion threshold in critical illness [26] and by diuretic administration. The ionized fraction is believed to be the physiologically active and homeostatically regulated portion and may more closely reflect the intracellular Mg status [27]. A simple membrane system for measuring the protein-free ultrafilterable ion concentration has been developed (Amicon MPS-1; Amicon, Danvers, MA), and has been shown to provide an excellent approximation of the ionized Mg level [28, 29]. Direct measurement of intracellular levels has not been practical in clinical practice, but mononuclear blood cell Mg and other methods are being investigated in this regard [30].

About 30% to 40% of dietary Mg is absorbed in the small intestine. Magnesium is ubiquitous in foods, and dietary deficiency is uncommon but does occur in malnutrition. Magnesium homeostasis is regulated primarily by tubular reabsorption in the kidney. In hypomagnesemic states, Mg excretion is decreased to less than 1 to 2 meq/d. Maximum tubular reabsorption occurs at total serum concentration of 1.5 to 2.0 mg/dL; above this range the kidney rapidly excretes excess Mg. Thus during Mg replacement therapy much of the administered Mg is lost in the urine, increasing the Mg requirement to replete intracellular stores [22].

Sixty to 80% of intracellular Mg is complexed with ATP at any given time, so that cellular Mg content reflects ATP content [31]. Ischemic events, such as occur in CPB, cardiac arrest, and myocardial infarction, result in loss of both Mg and ATP [4]. Magnesium content may be reduced as much as 30% to 40% [11]. As an important cofactor for oxidative metabolism, its loss may contribute to ATP depletion and decreased availability of cellular energy. Magnesium infusion after CPB maintains ATP levels, which are decreased when a Mg-deficient cardioplegic solution is used [32]. Magnesium-enriched cardioplegia solution has resulted in improved myocardial performance parameters, including stroke volume and cardiac index, after CPB [9, 33, 34]. In an isolated rat heart model, Mg added to cardioplegia solution enhanced recovery of cardiac function and resulted in a significant increase of intracellular ATP after hypothermic ischemic cardiac arrest [35]. Increasing the Mg concentration of the University of Wisconsin preservation solution to 15 mmol/L resulted in improved left ventricular function, coronary blood flow, and myocardial ATP content in an experimental model using rabbit hearts cold-stored for 40 hours [36]. Administration of ATP–MgCl2 improves cellular and organ function and survival in experimental shock and ischemia [37]. It is theorized that the positive effect of Mg in such situations is because of its ability to transfer phosphate between substrates resulting in regeneration of ATP [38]. The great majority of patients have been reported to be hypomagnesemic after CPB [39]. This is a result of both the ischemic insult and the hemodilution by large quantities of Mg-free fluids [9].

Magnesium is an essential cofactor for Na+–K+ transport. Its deficiency causes cellular efflux of K+ into the serum resulting in increased urinary K+ losses and hypokalemia [22]. Magnesium is required for cellular K+ repletion. Improved K+ homeostasis after Mg administration has been demonstrated in critically ill adults, who were noted to have much higher than normal urinary Mg losses [26].

Catecholamines exert their inotropic effects by influencing the activity of the membrane-bound adenylate cyclase enzyme system. The separate components of this system are interdependent and include the hormone receptor, a regulatory protein site, and a catalytic site [3, 40, 41]. An Mg-binding site is reported to exist on the regulatory protein [40]. The catecholamine binds to the hormone receptor, activating the adenylate cyclase, which catalyzes the intracellular conversion of Mg-ATP to 3`,5` cyclic adenosine monophosphate (Fig 3Go). Cyclic adenosine monophosphate, acting as second messenger, phosphorylates protein kinases that produce the cell-specific response to the hormone [3, 41]. In the case of cardiac muscle the response is increased sarcoplasmic reticulum (SR) calcium-channel conductance, resulting in enhanced contractile activity. Magnesium is required for adenylate cyclase activity and has been shown to enhance ß-adrenergic agonist effects [18, 40, 42]. In experiments using a frog erythrocyte membrane model, free Mg enhanced ß-adrenergic agonist binding affinity for adenylate cyclase-coupled hormone receptors by 20-fold, markedly potentiating the catalytic activity [40]. Magnesium is required for the inotropic effects of epinephrine [43].



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  		Fig 3. . Adrenergic receptor complex. When engaged by the appropriate hormone the receptor unit associates with the regulatory G protein, activating adenylate cyclase. Magnesium is required for adenylate cyclase activity. (ATP = adenosine triphosphate; 3`5` cAMP = 3`,5` cyclic adenosine monophosphate).

 
Seelig and Heggtveit [11] noted the importance of Mg for mitochondrial function and reported that cardiac Mg depletion from either ischemia or cardiotoxic drugs resulted in mitochondrial swelling, disorganization, and disruption. They noted that large doses of catecholamines caused cellular influx of calcium, followed by depletion of high energy phosphate content of heart muscle before the development of necrosis; MgCl2 was protective against excessive calcium uptake and structural damage [11]. They concluded that Mg had important metabolic effects in ischemic heart disease related to maintenance of subcellular structures and functions. Thus, adequate Mg supplementation may be essential for patients receiving infusions of calcium and catecholamines after ischemia.

Sepsis was suspected in this patient, and blood cultures were positive. Magnesium deficiency has been associated with a three-fold increase in lethality in experimental sepsis, but sepsis also appears to alter Mg distribution such that serum levels are increased, making detection of tissue Mg deficiency difficult [44]. In rodent and hamster models of Mg deficiency increased concentrations of the cytokines interleukin-1, interleukin-6, and tumor necrosis factor-{alpha}, and of substance P, have been demonstrated [45]. There is experimental evidence that Mg is essential for a number of immunological functions including macrophage activity [46], granulocyte oxidative burst [47], lymphocyte proliferation [48], and endotoxin binding to monocytes [49]. White and Hartzell [50] found that decreased Mg in myocytes was associated with efflux of Ca from SR into the cytosol and suggested that Mg may be important in regulating sepsis-associated Ca entry through Mg-dependent Ca ion channels. Wu and Li [51] reported that ATP-dependent Ca uptake by SR was inhibited by endotoxin, and this effect was reversible by Mg administration.

Shortly before decompensation, maintenance digoxin therapy had been resumed in our patient. The inotropic and antiarrhythmic effects of digitalis are attributed to inhibition of Na+–K+ ATPase, resulting in decreased concentration gradients of Na+ and K+ across the cellular membrane and an increase of intracellular calcium [52–54]. Magnesium is required for Na+–K+ ATPase function [3] (Fig 4Go). It is interesting to speculate about possible effects caused by the addition of digoxin to a cellular enzyme system already inhibited by a deficit of Mg. Perhaps this would not enhance inotropic activity, but rather have the opposite effect. A calcium gradient must exist between the SR and the intracellular space for the process of muscular contraction to occur. A Ca2+ ATPase in the SR membrane transports Ca out of the cytosol into the SR, essential to the contraction-relaxation cycles of muscle tissue [3]. Activation of this ATPase by Mg leads to a decrease of diastolic tone [55], whereas increased intracellular calcium concentration at the contractile apparatus causes enhanced affinity of actin-myosin cross bridges and disturbed diastolic tone [56]. The interaction of actin and myosin fibers absolutely requires ATP to permit dissociation of the myosin-actin complex, and hydrolysis by an ATPase to regenerate the myosin–adenosine diphosphate complex that cyclically binds and dissociates from actin [3]. An intracellular millieu of increased Ca concentration, loss of Ca gradient, saturation of troponin-Ca binding sites, bound myosin-actin complexes, dysfunctional ATPase activity, and ATP depletion would essentially be a condition of rigor mortis [3]. Digitalis intoxication promotes intracellular calcium overload [5, 53], as well as Mg deficiency by enhanced Mg excretion [7]. Magnesium deficiency enhances cardiac sensitivity to the toxic effects of digoxin [5, 11, 22].



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  		Fig 4. . Schematic representation of Na+–K+ adenosine triphosphatase. All mammalian cell membranes use adenosine triphosphate (ATP) hydrolysis for maintenance of ionic gradients. The Na+–K+ translocator has been estimated to use 60% to 70% of the ATP synthesized by nerve and muscle. A Ca2+ ATPase of sarcoplasmic reticulum similarly uses ATP hydrolysis to move Ca2+ from the cytosol to the sarcoplasmic reticulum, crucial to the contraction-relaxation cycles of muscle. (ADP = adenosine diphosphate; P = phosphate).

 
In summary, progressive cardiogenic shock developed in a 3-year-old child several days after CPB for surgical correction of congenital heart defects. The condition was initially unresponsive to ß-agonist inotropic therapy, but resolved dramatically after a bolus injection of MgSO4, even though total serum Mg had been in the normal range. Such a clinical event may be uncommon, but may illustrate potential serious adverse consequences of Mg deficiency. The precise mechanism by which MgSO4 exerted a beneficial effect is not known. Magnesium has numerous metabolic effects at the cellular level that could positively influence cardiovascular function. These include processes of cellular energy metabolism and enzyme functions involving ATP, maintenance of cell membrane functions, modulation of other intracellular ions, neuromuscular transmission, cardiac excitability, and vascular tone [6]. Improved cellular energy metabolism [4], enhanced responsiveness to catecholamines [40], modulation of intracellular Ca2+ ions [11], reciprocal antagonistic effects with calcium [17], improved coronary artery perfusion [57], and reduced systemic vascular resistance [13] may all have been relevant factors. Improved immune function may have contributed to long-term recovery [44]. The junctional rhythm observed postoperatively was not altered by Mg therapy and appeared related to the primary surgical injury.

Chronic malnutrition [7, 23], chronic diuretic use [23, 38, 58], and the known effects of CPB [9, 39] may all have contributed to the development of Mg deficiency in the patient reported here. The possible contribution by digoxin to the effects of Mg deficiency is interesting to consider. Routine measurements of total serum Mg are not helpful for determining intracellular Mg status, and newer methods of Mg measurement may develop clinical relevance [23, 27, 38]. It has been suggested that severely stressed patients have a much higher than normal daily Mg requirement and that the definition of normal serum Mg in the critically ill should be reassessed [26]. Magnesium deficiency is increasingly recognized in intensive care unit patients [2, 23, 59], and may be present despite normal serum levels, as in this patient. Critically ill patients with magnesium deficiency are claimed to have twice the mortality rate and a more rapidly fatal course [2]. Magnesium supplementation may have special relevance for critically ill patients receiving infusions of calcium and catecholamines [11]. Recognition of clinically significant Mg deficiency requires a high index of suspicion [38]. Magnesium deficiency should be considered in situations of refractory circulatory shock [60].


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Case Report
 Comment
 References
 
Address reprint requests to Dr Storm, MeritCare Children's Hospital, 720 Fourth St N, Fargo, ND 58122 (e-mail: wstorm{at}mail.med.und.nodak.edu).


   References
Top
 Footnotes
 Abstract
 Introduction
 Case Report
 Comment
 References
 

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