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Ann Thorac Surg 1999;68:2285-2291
© 1999 The Society of Thoracic Surgeons

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Original Articles

Superiority of magnesium cardioplegia in neonatal myocardial protection

^a Division of Cardiovascular Surgery, Heart Institute for Children, Hope Children’s Hospital, Oak Lawn, Illinois, USA

Address reprint requests to Dr Allen, Heart Institute for Children, Hope Children’s Hospital, 4440 W 95th St, Oak Lawn, IL 60453
e-mail: brad{at}thic.com

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. We have shown that magnesium can offset the detrimental effects of normocalcemic cardioplegia in hypoxic neonatal hearts. It is not known, however, whether magnesium offers any additional benefit when used in conjunction with hypocalcemic cardioplegia.

Methods. Twenty neonatal piglets underwent 60 minutes of ventilator hypoxia (FiO₂ 8% to 10%) followed by 20 minutes of normothermic ischemia on cardiopulmonary bypass (hypoxic-ischemic stress). They then underwent 70 minutes of multidose blood cardioplegic arrest. Five (Group 1), received a hypocalcemic (Ca⁺² 0.2 to 0.4 mM/L) cardiologic solution without magnesium, whereas in 10, magnesium was added at either a low dose (5 to 6 mEq/L, Group 2) or high dose (10 to 12 mEq/L, Group 3). In the last 5 (Group 4), magnesium (10 to 12 mEq/L) was added to a normocalcemic cardioplegic solution. Function was assessed using pressure volume loops and expressed as percentage of control.

Results. Compared to hypocalcemia cardioplegic solution without magnesium (Group 1), both high- and low-dose magnesium enrichment (Groups 2 and 3) improved myocardial protection resulting in complete return of systolic (40% vs 101% vs 102%) (p < 0.001 vs Groups 2 and 3) and global myocardial function (39% vs 102% vs 101%) (p < 0.001 vs Groups 2 and 3), and reduced diastolic stiffness (267% vs 158% vs 154%) (p < 0.001 vs Groups 2 and 3). Conversely, even high-dose magnesium supplementation could not offset the detrimental effects of normocalcemic cardioplegia resulting in depressed systolic (End Systolic Elastance [EES] 41% ± 1%) (p < 0.001 vs Groups 2 and 3) and global myocardial function (40% ± 1%) (p < 0.001 vs Groups 2 and 3), and a marked rise in diastolic stiffness (258% ± 5%) (p < 0.001 vs Groups 2 and 3). Hypocalcemic magnesium cardioplegia has now been used successfully in 247 adult and pediatric patients.

Conclusions. Magnesium enrichment of hypocalcemic cardioplegic solutions improves myocardial protection resulting in complete functional preservation. However, magnesium cannot prevent the detrimental effects of normocalcemic cardioplegia when the heart is severely stressed. This study, therefore, strongly supports using both a hypocalcemic cardioplegic solution and magnesium supplementation as their benefits are additive.

	Introduction

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The role of magnesium in cardioplegic solutions has predominately been studied experimentally and clinically in the adult heart using crystalloid cardioplegic solutions [1–5]. In the immature heart, our experimental studies show that either magnesium supplementation, or calcium depletion, provides improved protection in blood cardioplegic solutions [6, 7]. Indeed, there appears to be a specific interrelationship between magnesium and calcium that has led to the perception that magnesium may not be necessary when a hypocalcemic cardioplegic solution is used [1, 3, 4, 7]. Whether magnesium enrichment can improve the protection afforded by hypocalcemic blood cardioplegic solution therefore remains unanswered, especially in the immature heart. This study uses hypoxic ischemically damaged neonatal hearts to determine if there is improvement of myocardial protection when magnesium enrichment and hypocalcemia are combined in blood cardioplegic solutions. The data defines the specific benefits and limitations of either hypocalcemia or hypermagnesemia alone, and clarifies the endothelial, metabolic, and myocardial performance consequences of combining hypocalcemia and hypermagnesemia in blood cardioplegia. These results were then the sign post of our initial clinical evaluation of magnesium enrichment of our standard hypocalcemic blood cardioplegic solutions in 247 adult and pediatric patients.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Twenty neonatal (5 to 18 day old) piglets (3.5 to 5 kgs) were premedicated with 40 mg/kg ketamine intramuscularly, anesthetized with 30 mg/kg phenobarbital intraperitoneally, followed by 5 mg/kg intravenously each hour, and the lungs ventilated via a tracheotomy using a volume ventilator (Servo 900B, Siemens/Elema, Solna, Sweden). All animals received humane care in compliance with the principles ("Principles of Laboratory Animal Care") formulated by the National Society for Medical Research, and "Guide for the Care and Use of Laboratory Animals," prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH), Publication No. 96-03, Revised 1996. The experimental preparation, including cannulation for bypass and blood sample procurement, is comparable to that previously described [6, 7].

Experimental protocols
Hypoxic-ischemic injury
All piglets underwent 60 minutes of ventilator hypoxia by lowering the fraction of inspired oxygen (FiO₂) to 8% to 10% producing an arterial PO₂ of 25 to 35 mm Hg and an oxygen saturation (SaO₂) of 65% to 70%. Before hypoxemia, piglets were transfused as necessary to increase their hematocrit to greater than 35%. This simulates the chronic adaptive change of erythrocytosis and increases oxygen carrying capacity, thereby allowing ischemia to be avoided during hypoxia [6, 7]. At the end of 60 minutes, piglets were placed on cardiopulmonary bypass (CPB) at an FiO₂ of 100% for 5 minutes to produce a reoxygenation injury [6–8]. The aorta was then clamped for 20 minutes at 37°C to add a normothermic ischemic injury to the hypoxic stress. Piglets then underwent 70 minutes of cardioplegic arrest using the protocol described below.

Cardioplegia administration
Cardioplegia solutions (CAPS Service, Research Medical Inc, Salt Lake City, UT) are shown in Tables 1 and 2. Following the 20 minute normothermic-ischemic insult (see above), piglets underwent 70 minutes of cardioplegic arrest using a protocol consisting of 5 minutes of warm (37°C) induction (Table 1) followed by 4 minutes of cold multidose cardioplegia (Table 2), a 2 minute cold multidose infusion every 20 minutes, and a 4-minute warm (37°C) cardioplegic reperfusate ("hot shot") before aortic unclamping. Cardioplegia was always infused at a continuously measured aortic root pressure of 40 to 50 mm Hg. Immediately after cross clamping the aorta, all piglets were cooled to a systemic temperature of 26°C, and warming to 37°C was begun 16 minutes before aortic unclamping. All piglets were weaned from CPB with no inotropic support 30 minutes after aortic unclamping. After arterial blood gases, Ca⁺², and K⁺ were normalized, final functional and biochemical measurements were made 30 minutes later.

Low Ca⁺²/No Mg⁺² (Group 1): Five piglets received a hypocalcemic blood cardioplegic solution without magnesium.

Low Ca⁺²/Low Mg⁺² (Group 2): Five piglets received a hypocalcemic cardioplegic solution enriched with 5 to 6 mEq/L of magnesium (low dose).

Low Ca⁺²/High Mg⁺² (Group 3): Five piglets received a hypocalcemic cardioplegic solution enriched with 10 to 12 mEq/L of magnesium (high dose).

High Ca⁺²/High Mg⁺² (Group 4): The final 5 piglets received a normocalcemic cardioplegic solution enriched with 10 to 12 mEq/L of magnesium (high dose).

Myocardial oxygen consumption
After cardioplegic arrest, blood was obtained at 1 minute intervals from the cardioplegic line and coronary sinus over the 5 minutes of warm cardioplegic induction (Groups 1 to 3) and myocardial oxygen consumption (MVO₂) was determined as previously described [9]. The cumulative 5-minute MVO₂ was determined by the sum of the individual 1-minute values and expressed per 100 grams of heart tissue, which was determined by weighing the left ventricle at the conclusion of the experiment.

Myocardial performance
Left ventricular (LV) pressure and conductance catheter signals were amplified and digitized to inscribe LV pressure volume loops after first correcting for parallel conductance (myocardial tissue and blood viscosity) using hypertonic saline. A series of pressure volume loops was generated by transient occlusion of the inferior vena cava during an 8-second period of apnea. Measurements were made before hypoxia (baseline) and 30 minutes after cardiopulmonary bypass was discontinued. The end systolic and end diastolic pressure volume relationship and the preload recruitable stroke relationship were analyzed as previously described [6, 7]. Functional measurements are expressed as percent recovery of baseline values with each piglet acting as its own control. After final hemodynamic measurements, piglets were placed back on bypass and transmural LV biopsies obtained. Endocardial and epicardial portions were separated, frozen quickly in liquid nitrogen, and stored for biochemical analysis. A separate sample was obtained for myocardial water.

Physiologic measurements
Coronary vascular resistance (CVR) was determined as previously described during each cardioplegic infusion by measuring coronary sinus pressure and cardioplegic flow once a constant infusion rate with an aortic root pressure between 40 and 50 mm Hg was achieved [6, 7].

Biochemical analysis
Adenosine pool
Myocardial samples were crushed in a liquid nitrogen cooled mortar and pestle and lyophilized. The adenosine pool was determined as described previously [6, 7]. Adenosine triphosphate (ATP) levels are expressed as µg/g dry tissue.

Myocardial water
Ventricular samples were placed in preweighed vials and dried to a constant weight at a temperature of 85°C. The percent myocardial water was then calculated as previously described [6, 7].

Clinical studies
The charts of 247 consecutive patients receiving magnesium enriched hypocalcemic blood cardioplegic solution were retrospectively reviewed to determine the clinical safety and efficacy of this solution. There were 179 adult and 68 pediatric patients, and the preoperative demographics and operations performed are depicted in Table 3. The cardioplegic solutions are the same as those used experimentally, except that the warm solution contained a delivered concentration of 10 to 12 mEq/L of magnesium, whereas the cold multidose solution only contained 5 to 6 meq/L of magnesium. An integrated cardioplegia strategy that has been described previously was used in all adult patients [10, 11]. This strategy incorporates warm and cold cardioplegia, antegrade and retrograde delivery, and continuous and intermittent infusions. Pediatric patients received cold multidose blood cardioplegia delivered every 10 to 15 minutes and a terminal warm substrate enriched reperfusate. Retrograde delivery was given in any pediatric patient where antegrade infusions were not possible every 10 to 15 minutes (ie, arterial switch procedures).

	Results

Top Abstract Introduction Material and methods Results Comment References

 
There was no difference between groups for prehypoxic (baseline) values of left ventricular contractility, (35 ± 2) diastolic compliance, (0.04 ± 0.01), or preload recruitable stroke work (71 ± 3). All piglets remained stable during the 60 minutes of hypoxia.

Hemodynamic and physiologic measurements
Results are depicted in Figures 1 through 4. There was no change or difference in the X-axis intercept point (V₀) for end systolic elastance (pre 6.9 ± 0.1, post 6.8 ± 0.2) or preload recruitable stroke work (pre 10.6 ± 0.2, post 10.7 ± 0.1) between pre (baseline) and postbypass values in any experimental group. Therefore, the change in slope of end systolic elastance and preload recruitable stroke work can be interpreted to express variability in the contractile state of the myocardium compared to baseline values. Hypocalcemic blood cardioplegia without magnesium (Group 1) was unable to resuscitate the severely stressed (hypoxic-ischemic) myocardium resulting in decreased postbypass systolic contractility, markedly increased diastolic stiffness, and reduced preload recruitable stroke work. In contrast, hypocalcemic cardioplegia supplemented with low-dose (5 to 6 mEq/L, Group 2), or high-dose (10 to 12 mEq/L, Group 3) magnesium resuscitated and protected the severely stressed myocardium resulting in complete return of systolic function, and preloaded recruitable stroke work, and minimally increased diastolic stiffness. These values (Groups 2 and 3) were not statistically different (p < 0.2) from each other, indicating a similar beneficial effect with either dose. However, magnesium was not able to offset the detrimental effects of normocalcemic cardioplegia (Group 4) resulting in depressed systolic contractility and preload recruitable stroke work, and increased diastolic stiffness. Coronary vascular resistance was lower and similar in piglets receiving hypocalcemic magnesium cardioplegia (Groups 2 and 3), whereas it was increased in piglets receiving hypocalcemic cardioplegia alone (Group 1), or magnesium enriched normocalcemic cardioplegic solution (Group 4).

View larger version (19K): [in this window] [in a new window]   Fig 1. Left ventricular systolic function as measured by the end systolic elastance (EES) and expressed as percent of recovery of baseline values. Hearts protected with a hypocalcemic cardioplegic solution alone exhibited marked loss of systolic function. In contrast, there is complete preservation of systolic function when magnesium is added to hypocalcemic cardioplegic solution. However, magnesium enrichment was not able to offset the detrimental effects of a normocalcemic cardioplegic solution, resulting in diminished systolic function. *p < 0.001.

View larger version (18K): [in this window] [in a new window]   Fig 2. Left ventricular diastolic compliance as measured by the end diastolic pressure–volume relationship, and expressed as a percentage of stiffness compared to baseline values. There is a marked increase in diastolic stiffness in hearts protected with a hypocalcemic cardioplegic solution without magnesium. In contrast, there is only a minimal increase in diastolic stiffness in hearts protected with a magnesium enriched hypocalcemic cardioplegic solution. However, this improvement is negated when magnesium is added to a normocalcemic cardioplegic solution. *p < 0.001.

View larger version (19K): [in this window] [in a new window]   Fig 3. Overall left ventricular myocardial function measured by preload recruitable stroke work (PRSW) and expressed as percent recovery compared to baseline values. *p < 0.001.

View larger version (15K): [in this window] [in a new window]   Fig 4. Coronary vascular resistance (CVR) measured during each cardioplegic infusion, once the pressure and flow were stable. (See text for details.) *p < 0.001.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Magnesium, the second most abundant intracellular ion, is lost during ischemia, leading to an increase in postoperative arrhythmias and possible impairment of magnesium-dependent cellular reactions [3–5, 7, 12]. Replacing extracellular magnesium by enriching cardiologic solutions has been shown to decrease the incidence of postoperative arrhythmias, as well as improve myocardial protection by a variety of pathways [1, 3–5, 7, 12]. The most important of these is probably magnesium’s ability to modulate intracellular calcium levels by inhibiting calcium entry across the cellular membrane, as well as displacing calcium from the binding sites of the sarcolemmal membrane [1, 3, 4, 7]. This prevents mitochondrial calcium uptake, which can lead to uncoupling of oxidative phosphorylation with a decrease in ATP production. Postischemic calcium entry is further limited because magnesium prevents an influx of sodium, which during reperfusion is exchanged for calcium. Reducing calcium entry may be even more important in neonatal hearts because of the decreased ability of the immature heart to sequester excess calcium [13, 14]. Supplemental magnesium can also facilitate asystole at lower potassium concentrations [10]. This is important because high potassium concentrations can damage vascular endothelial cells directly, as well as enhance endothelial and myocyte calcium entry.

Although hypocalcemic blood cardioplegia without magnesium completely protects the hypoxic neonatal heart, this same solution was unable to adequately protect hearts subjected to hypoxia and ischemia [6, 7]. However, adding magnesium to the hypocalcemic cardioplegic solution markedly improved myocardial protection resulting in complete recovery of metabolic and myocardial function despite this severe (hypoxic/ischemic) "stress." This beneficial effect occurred at either low (5 to 6 mEq/L) or high (10 to 12 mEq/L) magnesium concentrations, and is similar to the improved results obtained when calcium channel blockers were used to retard calcium entry [10, 15]. Calcium channel blockers however, have a prolonged effect, which may depress postoperative function, making them less attractive. Because calcium and magnesium have an interrelationship, similar results might have been obtained in the absence of magnesium by further lowering the cardioplegic calcium concentration. However, myocardial recovery may be reduced when the cardioplegic calcium is less than 100 µmol/L, and although unlikely, a calcium paradox can occur if levels are reduced to less than 50 mmol/L [4, 10, 15–17]. The delivered cardioplegic calcium level was achieved by normalizing calcium in the bypass circuit. If a hypocalcemic bypass prime is used, the amount of citrate in the cardioplegic solution should be adjusted to produce the delivered concentrations found in Tables 1 and 2.

In contrast to our previous study, magnesium supplementation could not offset the detrimental effects of normocalcemic cardioplegia in severely stressed (hypoxic-ischemic) neonatal hearts [7]. Damage occurred despite using a relatively high concentration of magnesium (10 to 12 mEq/L). Because calcium and magnesium, however, do have an interrelationship, it is possible that a higher dose of magnesium would have improved recovery. This may explain why Hearse and colleagues found a magnesium dose of 16 mEq/L provided the best protection when used with normocalcemic crystalloid cardioplegia [1]. The optimal dose of magnesium therefore probably depends on the cardioplegic calcium concentration in as much as the beneficial effects of magnesium and hypocalcemia are additive as well as interdependent.

Because hypoxia and ischemia change both myocyte as well as endothelial cell function, we measured coronary vascular resistance with each cardioplegic infusion [6–8, 10, 18, 19]. Characteristically, an ischemic stress, or ischemia between cardioplegia doses, causes coronary vasodilation with a decrease in coronary vascular resistance [10]. Despite this, the coronary vascular resistance was increased with either a hypocalcemic blood cardioplegic solution without magnesium (Group 1), or a normocalcemic solution (Group 4). Conversely, the coronary vascular resistance was reduced if a hypocalcemic blood cardioplegic solution was supplemented with magnesium (Groups 2 and 3). These findings imply endothelial cell vascular dysfunction if the magnesium/calcium interaction is absent. Assessing CVR during cardioplegic infusions allows us to determine the response of the coronary vasculature to each cardioplegic solution. Although an elevated CVR is suggestive of a vascular injury, this cannot be proved, because specific tests of endothelial cell function were not done after bypass. However, an altered vascular response during cardioplegic infusions may affect myocardial protection by altering cardioplegic distribution. This, along with a vascular injury, probably explains the direct correlation between an elevated CVR and postbypass myocardial dysfunction.

This study uses both an ischemic and hypoxic stress because either hypocalcemic or hypermagnesemic blood cardioplegia alone is able to completely protect the neonatal heart subjected only to acute hypoxia [7]. Furthermore, the combination of hypoxia and ischemia may more closely resemble the cyanotic child because our model of acute hypoxia does not result in ischemia or ATP depletion, whereas the cyanotic infant or chronically hypoxic animal usually has depressed ATP levels [6, 8, 20–22]. This may explain why we saw greater oxygen-free radical production with reoxygenation of cyanotic infants compared to acute hypoxic animals, and why cyanotic infants often have postbypass myocardial dysfunction after apparently successful surgical repair [23, 24]. Even if a hypoxic-ischemic stress does not exactly mimic the cyanotic infant, it allows us to investigate cardioplegic solutions in stressed hearts. This is important as most neonatal hearts are not "normal" at the time of surgery, but are stressed by hypoxia or pressure volume overload.

Based on the experimental infrastructure provided by this as well as other reports, we began using magnesium-enriched hypocalcemic cardioplegic solutions in our adult and pediatric patients with excellent results [1, 3–5, 7]. The object of reporting this data is to document the safety of this solution, not to compare it with a control group. Lack of a control group should not negate our findings, as we believe there is sufficient experimental and clinical infrastructure demonstrating the efficacy of magnesium enrichment of cardioplegic solutions to improve protection and prevent postoperative arrhythmias [3–5, 7, 12]. Although the present experimental study suggests that a magnesium concentration of 5 to 6 mEq/L is adequate, we used a higher concentration (10 to 12 mEq/L) in our clinical warm cardioplegic solutions for several reasons. Normothermic hearts require higher potassium levels to maintain asystole during cardioplegic induction or terminal reperfusion (hot shot) [10]. Because high potassium levels can directly injure endothelial cells, as well as predispose to calcium influx, a higher concentration of magnesium allows the potassium concentration to be reduced while maintaining myocardial arrest [3, 7, 16, 17, 25]. When the heart is warm, ion fluxes and cellular reactions are faster, and the cell is more susceptible to a reperfusion injury [10]. It is in this setting that we previously demonstrated that lower cardioplegic calcium concentrations, as well as calcium channel blockers, were important [10, 15]. Because magnesium competes with calcium, higher magnesium concentrations should be beneficial for the same reason [3, 4]. Higher magnesium concentrations should also provide greater protection against postoperative arrhythmias, and Hearse and coworkers, and others, have documented that magnesium concentrations as high as 16 mEq/L are safe in both adult and pediatric patients [1, 3–5, 12].

In summary, the protective effects of magnesium and hypocalcemic blood cardioplegia are additive resulting in complete myocardial recovery, even in severely stressed hearts. The use of these two modalities is also safe in adult and pediatric patients. Based on this as well as numerous other reports, we believe magnesium should be routinely added to hypocalcemic blood cardioplegic solutions.

	Acknowledgments

 
This study was supported in part by the Pillsbury Fellowship. All experimental and clinical investigations were performed at the Heart Institute for Children and the University of Illinois at Chicago.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Bradley S. Allen Ari O. Halldorsson Gerald D. Buckberg Michel N. Ilbawi Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kronon, M. T. Articles by Ilbawi, M. N. Search for Related Content PubMed PubMed Citation Articles by Kronon, M. T. Articles by Ilbawi, M. N.