ORIGINAL ARTICLES
Hypomagnesemia Linda S. Aglio,
Is Common Following
Cardiac Surgery
MD, Gregory G. Stanford, MD, Rosemarie Maddi, MD, John L. Boyd Ill, MD, Samuel Nussbaum, MD, and Bart Chernow, MD, FACP
Hypomagnesemia is a common disorder in noncardiac surgical patients in the postoperative period, but the effect of cardiac surgery on serum magnesium concentrations remains unclear. The authors hypothesized that cardiac surgery is associated with hypomagnesemia, and prospectively studied 101 subjects (80 2 13.1 years of age) undergoing coronary artery revascularization (n = 70). valve replacement (n = 24), or both simultaneously (n = 7). Blood samples and clinical biochemical data were collected before induction of anesthesia, prior to cardiopulmonary bypass (CPB), immediately after CPB, and on postoperative day 1. Blood samples were analyzed for ultrafilterable magnesium, total magnesium, ionized calcium, parathyroid hormone, and free fatty
T
HE IMPORTANCE of the divalent cations calcium and magnesium in myocardial cell function has been known for decades, but the need for measurement and maintenance of extracellular concentrations of these ions in patients with cardiac disease remains controversial.‘,’ Calcium is frequently administered for its inotropic effect after cardiopulmonary bypass (CPB) even though the use of calcium salts for this indication has recently been challenged with arguments both for’ and against its use.L3 The role of magnesium in cardiovascular function has not been as extensively studied as the role of calcium, but its importance has been receiving increasing attention. Patients with a magnesium deficiency have an increased incidence of supraventricular and ventricular dysrhythmias,4a5and magnesium salts are now the recommended treatment for a particularly troublesome ventricular dysrhythmia, torsade de pointes.6 Patients with hypomagnesemia have a higher incidence of potentially lethal dysrhythmias following myocardial infarction (MI) than patients with a normal serum magnesium concentration.’ Magnesium infusions in patients following MI decrease potentially lethal dysrhythmias’,’ and decrease mortality.* Magnesium infusions in dogs lower heart rate, decrease cardiac contractility and coronary blood flow, and markedly decrease myocardial oxygen consumption and myocardial oxygen extraction.9 The effect of CPB on magnesium balance is not known. Magnesium administered during CPB may decrease calcium influx through calcium channels and in so doing may potentiate potassium cardioplegia during cardiac surgery.‘0-‘2 In the isolated rat heart, magnesium displays a marked dose-dependent protective effect on ischemic myocardium.” Magnesium use in the pump prime (instead of calcium) significantly improves myocardial performance when compared with a pump prime using calcium.”
acid concentrations. Outcome variables were also determined. Eighteen of gg (18.2%) subjects had hypomagnesemia preinduction and this number increased to 71 of 100 (71.0%) following cessation of CPB (P < 0.05). Patients with postoperative hypomagnesemia had a higher frequency of atrial dysrhythmias (22 of 71 [31.0%] v 3 of 29 [10.3%], P < 0.05) and required prolonged mechanical ventilatory support (22 of 83 [34.g%] v 4 of 33 [12.1%], P < 0.05). Hypomagnesemia is common following cardiac surgical procedures with CPB and is associated with clinically important postoperative morbidity. Copyright 0 1991 by W. 6. Saunders Company
Because patients undergoing CPB may be at increased risk of hypomagnesemia and because these patients may not tolerate hypomagnesemia as well as other critically ill patients, it was hypothesized that hypomagnesemia is a frequent occurrence in cardiac patients. To test this hypothesis, magnesium homeostasis was prospectively studied in a large group of cardiac surgical patients. The authors have previously described clinically important hypomagnesemia in critically ill adultI and pediatric patients.” In this report, those studies have been extended to another group of critically ill patients: those patients recovering from cardiac surgery involving CPB. MATERIALS
AND METHODS
Patients over the age of 18 years electively scheduled for cardiac surgery that would require CPB were invited to participate in the
This article is accompanied by an editorial. Please see: Finlayson DC: Magnesium: Its time has come. J Cardiothorat Vast Anesth 5:199-200,199l
From the Department of Anesthesia, Brigham and Women S Hospital/Harvard Medical School, and the Departments of Anesthesia and Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA. Supported in part by funds from the Hemy IL Beecher Memorial Anesthesia Research Laboratories of the Massachusetts General Hospital, Boston, MA. Address reprint requests to Linda S. Aglio, MD, Depatiment of Anesthesia, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02114. Copyright o 1991 by W B. Saunders Company 1053-0770/91/0503-0002$03.00/0
AGLIO ET AL
202
study. The study was approved by the Institutional Review Board at the study hospital, and all patients signed written informed consent. Following admission to the study, a complete history was recorded with particular attention to predisposing illnesses and drugs known to affect magnesium metabolism. Patients were then followed by study personnel throughout their hospitalization, and all complications and adverse reactions were carefully monitored and recorded. Particular attention was paid to those complications that could be related to magnesium dyshomeostasis including postoperative dysrhythmias, MI, congestive heart failure, respiratory failure, excessive potassium requirements, hypocalcemia, sepsis, and death. These complications were determined using standard definitions (Table 1). Table 1. Criteria for Complications Sepsis?
Patients who meet the following criteria are classified
as having a septic episode Clinical evidence of infection Fever
(> 38.3”C
rectal) or hypothermia
Tachycardia (>90
(< 35.6”C
rectal)
beats/min)
Tachypnea (>20 breathdmin while breathing spontaneously) At least one of the following manifestations of inadequate organ perfusion or organ dysfunction Altered mentation (in relation to patient’s baseline) Hypoxemia (arterial oxygen tension the
upper limit of normal for the labo-
ratory performing the assay) Oliguria (output ~30 mL or 0.5 mUkg for at least 1 hour) Myocardial Infarction4’,48: Patients having any of the following criteria are considered as having an acute myocardial infarction Classic electrocardiogram
changes including
The fresh appearance of Q waves or the increased prominence of preexisting ones ST segment elevation T wave inversions Serum CK-MB bands in excess of 5% of the serum total CK
Blood samples were collected from each patient at four time points. The first sample was obtained preoperatively before the induction of anesthesia (time 1). The second sample was obtained after the induction of anesthesia and after the skin incision had been made, but before the initiation of CPB (time 2). The third sample was collected after the completion of CPB (time 3). The fourth sample was collected on the morning of postoperative day I (time 4). Blood samples were immediately placed on ice, and the serum was separated and stored at -70°C until the assays were performed. The serum ionized calcium concentration was measured using an ion-specific selective electrode (Nova II, Nova Biomedical, Waltham, MA). The serum total magnesium concentration was measured using a specific spectrophotometric assay.‘” The normal serum total magnesium using this assay is 0.8 to 1.2 mmol/L (1.6 to 2.0 mEq/L). The serum ultrafilterable magnesium concentration was measured by placing 750 FL of serum into an Amicon Centifree micropartition filter system (Amicon Division, W.R. Grace and Co. Danvers, MA) followed by centrifugation at 3,000~ using a fixed-angle centrifuge. The protein-free filtrate was assayed for magnesium concentration using the same spectrophotometric assay as was used for the serum total magnesium concentration. The normal serum ultrafilterable magnesium concentration using this assay is 0.44 to 0.66 mmol/L (0.88 to 1.32 mEq/L). The serum parathyroid hormone (PTH) concentrations were measured using a specific and sensitive two-site immunoradiometric assay that detects the intact PTH molecule“ (Allegro, Intact PTH l-84, Nichols Institute Diagnostics, San Juan Capistrano, CA). This assay uses two affinity-purified polyclonal antibodies to quantitate accurately only the intact, circulating hormone. It has been found to be specific under conditions of a changing PTH concentration.” Serum free fatty acid concentrations were measured using an enzymatic assay (NEFA C. Wako Pure Chemical Industries, Ltd. Osaka, Japan). Serum potassium concentrations were measured using an automated analyzer. Statistical analysis of discrete variables was performed using x’ analysis and Fisher’s exact test. Continuous variables were analyzed using an analysis of variance for repeated measures over time. A P value less than 0.05 was considered to be statistically significant. Unless otherwise noted, data are expressed as mean ? SD.
or greater than 50 IU/L in the first 30 hours after surgery Serum LDHJLDH, greater than 1 .OOon two separate samples
RESULTS
24 to 48 hours after surgery Dysrhythmias4’
Overall Patient Population
Supraventricular: Disturbances of rhythm originating in the atrium or atrioventricular junction characterized by normal QRS complexes unless complicated by aberrant ventricular conduction Ventricular: Disturbances of rhythm originating in the ventricles associated with bizarre QRST complexes with prolonged QRS intervals. Heart Failure4’?
Patients with the following criteria are desig-
nated as having diminished cardiac function Pulmonary artery wedge pressure > 18 mm Hg Cardiac index < 2.2 L/min/m2 Acute Renal Failure”: Patients who have a serum creatinine > 2.5 mg/dL with previously normal renal function or an increase in the serum creatinine >2.0 mg/dL in the presence of chronic renal insufficiency and who meet one of the following criteria are designated as having acute renal failure Urine output ~30 mL/h with an adequate intravascular volume and in the absence of obstruction Urine osmolality 2.0 (RF1 = U/P Na divided by U/P creatinine x 100)
A total of 101 patients were entered into the study. The mean age of the study population was 60.4 t 13.1 years (range, 22 to 84 years). There were 82 men and 19 women. Seventy patients underwent coronary artery bypass grafting (CABG), 24 patients underwent either aortic or mitral valve replacement, and 7 patients had combined CABG and valve replacement. Twelve patients had undergone previous cardiac surgery, but none of these operations occurred within the 12 months prior to this study. A summary of the complications is shown in Table 2. The most common postoperative complications were dysrhythmias, which occurred within 24 hours of surgery in 49 of 101 (48.5%) patients. Twenty-three of 101 (22.8%) patients developed atria1 dysrhythmias only, 23 of 101 (22.8%) patients developed ventricular dysrhythmias only, and 3 of 101 (3.0%) patients developed both atria1 and ventricular dysrhythmias. Respiratory failure defined as the requirement for mechanical ventilation longer than 24 hours after
HYPOMAGNESEMIA
203
FOLLOWING CARDIAC SURGERY
Table 2. Comparison of Complications Between Patients With Normal and Low Total Serum Magnesium Concentrations Time 4
Time 3
Complication
at Times 3 and 4
No. With
No. With
No. With
Low Mg++
Normal Mg++
Low Mg++
Normal Mgtt
29/100 (29.0%)
63/96* (65.6%)
33/96 (34.4%)
No. With
Total patients
71/100*
Atrial dysrhythmias
22171 ?? (31.0%)
3/29
(10.3%)
18/63
(28.6%)
El33 (24.2%)
Ventricular dysrhythmias
19171
(26.8%)
7/29
(24.1%)
16/63
(25.4%)
10/33 (30.3%)
Congestive heart failure
7/71
(9.8%)
4/29
(13.8%)
El63
(12.7%)
3/33 (9.1%)
Sepsis
7/71
(9.8%)
l/29
(3.4%)
6/63
(9.5%)
21171
(29.6%)
5/29
(17.2%)
Death
a/71
(11.3%)
5/29
(17.2%)
3/63
(4.8%)
Hypocalcemia
5/71
(7.0%)
2/29
(6.9%)
14/63
(22.2%)
6/33 (18.2%)
34171
(47.9%)
16/29
(55.2%)
43/63
(68.2%)
24133 (72.7%)
51171
(71.8%)
22/29
(75.9%)
46/63
(73.0%)
28/33 (84.8%)
Ventilatory support > 24 h
Increased free fatty acids
(71 .O%)
22/63* (34.9%)
2/33 (6.1%) 4/33 (12.1%) 6/33 (18.2%)
Required > 100 mEq K’ over postoperative day 1 ?? P < 0.05 when comparing the hypomagnesemic
patients with the normomagnesemic
surgery was also common. Eleven of 101 (10.9%) patients developed congestive heart failure and 10 of 101 (9.9%) patients had postoperative MIS. Thirteen of the 101 patients died during the study period. Other complications included a cerebrovascular accident in one patient and a postoperative small bowel obstruction requiring reoperation in another patient. Nine patients developed the sepsis syndrome, but only one of these patients died. One patient with chronic renal failure developed acute renal failure postoperatively. Serum Total Magnesium (Hypomagnesemic v Normomagnesemic Patients)
Blood samples were not available for a small number of patients at all time points because of mortality, and because, on occasion, an insufficient sample for the magnesium or ultrafilterable magnesium assays remained after other laboratory tests had been performed. Nineteen of 99 (19.2%) patients had serum total hypomagnesemia prior to the induction of anesthesia (Fig 1). This number increased to 31 of 98 (31.6%) patients after the induction of anesthesia and surgery, but prior to CPB; this increase was not statistically significant. A significantly greater number of patients were hypomagnesemic after CPB (71/100 patients, 71%) when compared with the number of hypomagnesemic tota!pati.9nfs=lOl-
Fig 1. Numbers of patients with serum total ??and ultrafilterable 0 hypomagnesemia at each time point in the study. Time 1, baseline immediately prior to surgery; time 2, after the beginning of surgery but before CPB; time 3, after completion of CPB; time 4, postoperative day 1. ?? P 5 0.05 compared with baseline.
patients at the same time point.
patients preoperatively (P < 0.05). The number of hypomagnesemic patients remained significantly increased into postoperative day 1 (63/96 patients, 65.6%; P < 0.05). A comparison of the complications in the hypomagnesemic group (those patients with total serum magnesium concentrations less than 0.8 mmol/L at time 3 and/or time 4) versus the normomagnesemic group is shown in Table 2. A significantly greater number of patients who were hypomagnesemic at time 3 had atria1 dysrhythmias in the postoperative period (P < 0.05). Hypomagnesemia was not more common in patients with ventricular dysrhythmias. Those patients whose hypomagnesemia persisted into postoperative day 1 required prolonged ventiiatory support (mechanical ventilation longer than 24 hours after surgery). Patients who developed congestive heart failure postoperatively had a higher frequency of hypomagnesemia at time 2 (P < 0.05), but not at either time 3 or time 4. Hypomagnesemia was not associated with increased free fatty acid concentrations or hypocalcemia. Although the need for large amounts of potassium supplementation was common in this patient population, it was not significantly associated with hypomagnesemia. Hypomagnesemia was not more common in those patients who died, and none of these deaths could be directly attributed to complications related to hypomagnesemia. A comparison of risk factors for hypomagnesemia is provided in Table 3. A significantly greater number of patients receiving chronic digoxin therapy were hypomagnesemic preoperatively (P < 0.05), but this difference did not persist throughout the study. Patients taking diuretics did not have a higher prevalence of hypomagnesemia preoperatively; however, this group did have a higher incidence of serum total hypomagnesemia at time 3 (P < 0.05). When the type of diuretic was analyzed, neither loop diuretics nor thiazide diuretics could be implicated as the cause of this hypomagnesemia after CPB. Patients who were receiving calcium antagonists preoperatively had a lower prevalence of hypomagnesemia at time 3, suggesting that these agents may in some way prevent the loss or redistribution of magnesium during CPB. A significantly higher number of diabetic patients were hypomagnesemic at the beginning of the study (P < 0.05).
AGLIO ETAL
204
Table 3. Comparison of Risk Factors for Hypomagnesemia
Between Patients With Normal and Low Total Serum Magnesium Concentrations
Time 1
Time 2
Time 3
Time 4 _-
No. With Risk Factor
Totalpatients
Low Mg+’
No. With Normal Mg
No. With
’
Low Mg+ +
No. With
Mg*
Normal
No. With
No. With
No. With
Low Mg’
Normal Mg
Low Mg’
No. Wtth
’
Normal Mg’
’
19/99 (19.2%) 80/99 (80.8%) 31198 (31.6%) 67/98 (68.4%) 711100 (71.0%) 291100 (29.0%) 63/96 (65.6%) 33196 (34.4%)
Diuretics All
5/19 (26.3%) 28/80 (35.0%) IO/31(32.2%) 23167 (34.3%) 28/71* (39.4%) 5/29 (17.2%) 21/63 (33.3%) 9/33 (27.3%)
Loop diuretics
5/19 (26/3%) 24/80(30.0%) 8/31 (25.8%) 21/67 (31.3%) 25171 (35.2%) 4129 (13.8%) 18/63(28.6%) 8/33 (24.2%)
Thiazidediuretics
2/19 (10.5%) 11/80(13.8%) 4/31 (12.9%) 9/67 (13.4%) 11/71 (15.5%) 2/29 (6.9%)
Calcium antagonists Digoxin
6/63 (9.5%)
4/33 (12.1%)
14/19 (73.7%) 49/80 (61.2%) 20/31 (64.5%) 41/67 (61.2%) 40/71* (56.3%) 24129 (82.8%) 45/63 (71.4%) 18/33(54.5%) 7/19* (36.8%) 13/80(16.3%) 6/31 (19.4%) 13/67(19.4%) 17171 (23.9%) 4/29 (13.8%) 13/63 (20.6%) 7/33 (21.2%)
Diabetesmellitus All
7/19* (36.8%) 12/80(15.0%) 5/31 (16.1%) 13167 (19.4%) 13/71 (18.3%) 6/29 (20.7%) 12/63(19.0%) 7/33 (21.2%)
Insulin-dependent
l/19 (5.3%)
2/80 (2.5%)
l/31(3.2%)
l/67(1.5%)
2/71 (2.8%)
1129 (3.4%)
2/63 (3.2%)
l/33(3.0%)
Noninsulin-dependent 6/19* (31.6%) lo/80 (12.5%) 4/31 (12.9%) 12/67 (17.9%) 11171 (15.5%) 5/29 (17.2%) lo/63(15.9%) 6/33 (18.8%)
?? P 5 0.05when comparing the hypomagnesemic patients with the normomagnesemic patients at the same time point.
However, this difference was present only at time 1, and the diabetic patients did not have an increased incidence of hypomagnesemia either at the conclusion of CPB or on postoperative day 1. The diabetic population was separated into insulin-dependent and noninsulin-dependent subsets and separately analyzed; only three patients had insulindependent diabetes, so statistical comparisons between the two groups were not meaningful.
terable hypomagnesemia at time 4 (P < 0.05), whereas there was no difference in those patients receiving thiazide diuretics. In contrast to the serum total magnesium, calcium channel antagonists had no effect on the serum ultrafilterable magnesium concentration. Similarly, diabetics and nondiabetics had similar ultrafilterable magnesium concentrations. DISCUSSION
Serum UltrafilterableMagnesium (Hypomagnesemic v Normomagnesemic Patients)
The serum ultrafilterable magnesium concentration was measured in order to determine if this variable was a better predictor of complications in cardiac surgical patients. Several samples could not be analyzed because insufficient serum was available after the ionized calcium and serum total magnesium concentrations had been obtained. There were a number of patients with decreased serum ultrafilterable magnesium concentration at times 1, 2, and 3; however, there were more patients with ultrafilterable hypomagnesemia at time 4 than patients with total hypomagnesemia. There was no correlation between the serum ultrafilterable magnesium concentration and the serum total magnesium concentration (Fig 2). A comparison of complications in patients with low and normal serum ultrafilterable magnesium concentrations is shown in Table 4. The significant finding was that patients with a low serum ultrafilterable magnesium concentration required large amounts of intravenous potassium ( > 100 mEq) in order to correct hypokalemia compared with those patients with normal ultrafilterable magnesium concentrations (P < 0.05). Patients with low ultrafilterable concentrations did not experience an increased incidence of atria1 dysrhythmias or prolonged ventilatory support compared with patients with normal ultrafilterable magnesium concentrations. The risk factors for the development of ultrafilterable hypomagnesemia are analyzed individually in Table 5. There were no statistical differences between the numbers of patients with normal and low ultrafilterable magnesium concentrations at any time point in patients taking diuretics. When the individual diuretic classes were examined, patients on loop diuretics had a lower incidence of ultrafil-
Magnesium is an important intracellular ion involved in numerous enzymatic and biochemical reactions. The heart requires magnesium for both pump function and proper action potential transmission. Cardiac surgery with CPB often involves an ischemic period to the myocardial cells. The effect of this ischemia and cellular hypoxia is lessened by hypothermia, but still results in impairment of cellular energy utilization. Following CPB, the recovery of myocardial cell function is dependent on the restoration of oxidative metabolism. Magnesium is an absolute require-
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1.5
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2.5
Total Mg (mmol/L) Fig 2. A comparison of simultaneous total magnesium concentration and ultrafilterable magnesium concentration assayed on all serum samples obtained during the study. Least squares regression analysis demonstrated no correlation between the two values: y = 0.16x + 0.37; r’ = 0.16.
HYPOMAGNESEMIA
205
FOLLOWING CARDIAC SURGERY
Table 4. Comparison of Complications Between Patients With Normal and Low Ultrafilterable
Serum Magnesium Concentrations
at
Times 3 and 4 Time 3 No. With Low Mg++
Complication
Time 4 No. With Normal Mg++
No. With Low Mg++
No. With Normal Mg++
Total patients
49/98 (50.0%)
49/98 (50.0%)
64187
(73.6%)
23187 (26.4%)
Atrial dysrhythmias
13/49 (26.5%)
12/49 (24.5%)
18164 (28.1%)
5123 (21.7%)
Ventricular dysrhythmias
9/49 (18.4%)
17149 (34.7%)
17164 (26.6%)
8123 (34.8%)
Congestive heart failure
6/49 (12.2%)
3/49 (6.1%)
7164 (10.9%)
l/23 (4.3%)
Sepsis
6/49 (12.2%)
l/49 (2.0%)
6164
14/49 (28.6%)
11/49 (22.4%)
Ventilatory support > 24 h
20/64
(9.4%)
l/23 (4.3%)
(31.2%)
5/23 (12.7%)
Death
4/49 (8.2%)
9/49 (18.4%)
3164 (4.7%)
Hypocalcemia
3/49 (6.1%)
4149 (8.4%)
12164 (18.8%)
27/49 (55.1%)
23/49 (46.9%)
49164
(76.6%)
18123 (78.3%)
37149 (75.5%)
34/49 (69.4%)
53/64* (82.8%)
13/23 (56.5%)
Increased free fatty acids
6/23 (26.4%) 4/23 (17.4%)
Required > 100 mEq K’ over postoperative day 1 *P < 0.05 when comparing the hypomagnesemic
patients with the normomagnesemic
ment of oxidative phosphorylation, and magnesium depletion may contribute to depletion of adenosine triphosphate (ATP) during relative hypoxia.‘9.20Magnesium has a protective role in experimental ischemia in isolated organ studies, and an increased magnesium concentration in the buffer maintains cellular ATP stores.19~2’~22 In humans, the addition of magnesium to the cardioplegia solution during cardiac surgery enhances recovery from the ischemic hypothermic arrest at the completion of surgery.‘* Magnesium may exert its cardiac effects through its influence on potassium and calcium channels. Several types of potassium channels allow potassium to pass more readily into the cell than out of the cell in a process called inward rectification.*’ This inward rectification may be caused by intracellular magnesium blocking the efflux of potassium from the ce11.*4~26 When the intracellular magnesium is depleted, the potassium channel loses its selectivity, and potassium can pass equally well into the cell as well as out of the cell. The intracellular magnesium may then act as a regulator of depolarization and repolarization, and alterations in magnesium concentrations would cause derangements in the propagation of action potentials leading to dysrhythmias. Table 5. Comparison of Risk Factors for Hypomagnesemia
patients at the same time point.
Magnesium may also function as a physiological calcium antagonist.*’ Intracellular calcium is normally sequestered in the sarcoplasmic reticulum and is released into the cytoplasm during cellular activation. The cell returns to the resting state by active calcium uptake of the sarcoplasmic reticulum as well as extrusion of calcium from the cell. The uptake of calcium by the sarcoplasmic reticulum is highly magnesium-dependent and is stimulated at low magnesium concentrations and inhibited by increasing intracellular magnesium.Z8 Because this sarcoplasmic uptake is a primary mechanism of regulating intracellular calcium, even minor changes in the intracellular magnesium concentrations will profoundly affect calcium fluxes and cardiac function. These altered calcium fluxes may explain the increased atria1 dysrhythmias observed in the hypomagnesemic patients in the early postoperative period (during the first 24 hours after surgery). Interestingly, hypomagnesemia is significantly associated with these dysrhythmias immediately after surgery and not on the first postoperative day. However, most atria1 dysrhythmias occur early after surgery with a decreasing incidence as the time from surgery increases. This clinical observation suggests that hypomagnesemia may act as a cofactor in the induction of these
Between Patients With Normal and Low Ultrafilterable
Serum Magnesium
Concentrations Time 1 RiskFactor Total patients
Time 2
Time 3 No. With Low Mg+’
No. With Normal Mg++
Time 4
With Low Mg++
No. With Normal Mg++
No. With Low Mg++
No. With Normal Mg++
14/92 (15.2%)
78/92 (84.8%)
22/92 (23.9%)
70/92 (76.1%)
49/98 (50.0%)
49/98 (50.0%)
64/87 (73.6%)
23/87
No.
No. With Low Mg++
No. With Normal Mg++ (26.4%)
Diuretics All
3/14 (21.4%)
29/78 (37.2%)
4/22 (18.2%)
28/70 (49.0%)
13/49 (26.5%)
20/49 (40.8%)
18/64 (28.1%)
12/23* (52.2%)
Loop diuretics
3/14 (21.4%)
25/78 (32.0%)
4/22 (18.2%)
24/70 (34.3%)
11/49 (22.4%)
18/49 (36.7%)
14/64 (21.9%)
12/23* (52.2%)
Thiazide diuretics
O/14 (0.0%)
12/78 (15.4%)
l/22 (4.5%)
11/70 (15.7%)
4/49 (8.2%)
9/49 (18.4%)
6/64 (9.4%)
5/23
(21.7%)
lo/14 (71.4%)
49/78 (62.8%)
13/22 (59.1%)
45/70 (64.3%)
35/49 (71.4%)
27/49 (55.1%)
43/64 (67.2%)
12/23
(52.2%)
4/14 (28.6%)
15/78 (19.2%)
5/22 (22.7%)
14/70 (20.0%)
lo/49 (20.4%)
11/49 (22.4%)
14/64 (21.9%)
6/23
(26.1%)
All
2/14 (14.3%)
13/78 (16.7%)
5/22 (22.7%)
13/70 (18.6%)
lo/49 (20.4%)
7/49 (14.3%)
12/64 (18.8%)
Insulin-dependent Noninsulin-dependent
l/14 (7.1%)
l/78 (I .3%)
2/22 (9.1%)
l/70 (1.4%)
2/49 (4.1%)
o/49 (0.0%)
2/64(3.1%)
3/23 O/23
(13.0%) (0.0%)
12/78 (15.4%)
3/22 (13.6%)
12/70 (17.1%)
8/49 (16.3%)
7149 (14.3%)
lo/64 (15.6%)
3/23
(13.0%)
Calcium antagonists Digoxin Diabetes mellitus
l/l4
(7.1%)
?? P 5 0.05 when comparing the hypomagnesemic
patients with the normomagnesemic
patients at the same time point.
AGLIO ET AL
rhythm disturbances. The other factors that may contribute to dysrhythmia induction include volume overload, hypovolemia, pH changes, and postcardiotomy irritability. Because the patient stabilizes over the early postoperative period and the presence of these cofactors disappears, it is speculated that hypomagnesemia has less of an effect on the myocardial conduction system. Magnesium concentrations have been measured in previous studies involving CPB. Killen et alZ9 measured total magnesium concentrations in 38 patients who received acid-citrate-dextrose (ACD) as a blood preservative in the pump prime. In that study, there was a marked depression of the plasma magnesium concentration that could be prevented by the addition of 10% magnesium sulfate in the amount of 3 mL/U of ACD blood returned to the patient. Postoperative complications were not mentioned. Holden et al”’ measured total magnesium concentrations in the serum of patients before and after cardiac and noncardiac thoracic surgery. Urine magnesium concentrations were also measured. Baseline serum magnesium concentrations were low in patients who had recently been in congestive heart failure. All patients had hypomagnesemia postoperatively, but those patients undergoing CPB had lower magnesium concentrations, which remained decreased for 3 postoperative days. Urine magnesium concentrations increased during CPB, but then decreased in the immediate postoperative period and remained decreased for the first 2 postoperative days. No definite relationship could be demonstrated between hypomagnesemia and postoperative complications. In a subsequent study, Holden” randomized patients to receive magnesium sulfate or a placebo after valve replacement surgery. The treatment group normalized their serum magnesium concentrations whereas the placebo group remained hypomagnesemic. The treatment group had fewer complications related to pacing difficulties, dysrhythmias, mental derangements, and peripheral neurological problems. There were no significant differences with respect to postoperative bleeding or urinary output between the two groups. Although this study involved a small number of patients, it was the first to show a beneficial effect of magnesium supplementation after cardiac surgery. In the present study, an association was found between hypomagnesemia and complications after cardiac surgery involving CPB. In addition, this study is the first to measure ultrafilterable magnesium concentrations in cardiac surgical patients. Because these patients have fluid shifts and rapid changes in plasma protein concentrations, the ultrafilterable magnesium concentration may be a more reliable measurement of the available magnesium. As has been found in previous studies comparing ionized calcium with total calcium concentration,” the ultrafilterable magnesium concentration was abnormal much less often than the total magnesium concentration in the study patients. Because at present there is no reliable means of measuring the ionized magnesium concentration, the ultrafilterable magnesium
concentration remains the closest approximation to the biologically active ionized magnesium concentration. The finding of such a high prevalence of hypomagnesemia after CPB (711100 patients) was surprising. Previous studies of serum total magnesium concentration in postoperative patients admitted to the intensive care unit found an incidence of 60%.” In the pediatric population, about 30% of critically ill children have hypomagnesemia.” The only previous operation found to be associated with postoperative hypomagnesemia is esophagogastrectomy. Cardiac surgical patients are a group that would be expected to have a high prevalence of hypomagnesemia because of the frequent use of drugs that adversely affect magnesium balance. The kidney is responsible for maintaining an adequate serum magnesium concentration, and about 65% of the magnesium filtered at the glomerulus is reabsorbed in the loop of Henle.” Not surprisingly, loop diuretics interfere with this reabsorption, causing clinically important renal losses of magnesium.i.‘4 Thiazide diuretics can also induce hypomagnesemia when used chronically.‘S’i In this study, 21 of 101 patients were receiving loop diuretics preoperatively. 5 patients received thiazide diuretics preoperatively, and 8 patients were receiving both types of diuretics. Baseline hypomagnesemia was not found to be more prevalent in the patients receiving these medications than in patients who were not receiving diuretics. However, the serum magncsium concentration may not adequately reflect the intracellular magnesium concentration. Other investigators have found lower magnesium concentrations in the heart muscle of patients after sudden coronary deaths when compared with trauma-related deaths.“-“’ which did not correlate with the serum magnesium concentration. The present patients may have had a decreased intracellular magnesium concentration that became clinically important after the stress of cardiac surgery. Another drug used commonly in cardiac surgical patients, digoxin. interferes with magnesium homeostasis by causing an increased efflux of magnesium from the cell through its action on Ca-Mg ATPase.“’ Hypomagnesemia can accentuate digitalis toxicity, and magnesium salts have been used successfully to treat digitalis toxicity.“’ Alcohol is used commonly in this society and results in increases in renal magnesium losses that can lead to chronic magnesium depletion.“’ Some cardiac surgical patients also may have associated illnesses that alter magnesium homeostasis. Patients with type I diabetes mellitus arc consistently hypomagnesemic,4’~1J which correlates inversely with the degree of control of hyperglycemia.” The cause of hypomagnesemia after cardiac surgery is unknown; however, as with hypocalcemia in critically ill patients? it is speculated that the cause of hypomagnesemia is probably multifactorial. The presence of hypomagnesemia after cardiac surgery may be a laboratory curiosity, but the authors believe that it is not the case. Future research should be directed at determining if correction of hypomagnesemia will decrease the incidence of postoperative complications. Previous work by Holden” suggests that correction of hypomagnesemia after cardiac surgery leads
HYPOMAGNESEMIA
FOLLOWING
CARDIAC
SURGERY
207
to decreased number and severity of complications. Magnesium decreases dysrhythmias after MI,’ which suggests that it may be beneficial after other ischemic insults. A study to investigate the use of exogenous magnesium therapy after
cardiac surgery is currently in progress. At the present, it is recommended that serum magnesium concentrations be followed closely after cardiac surgery and that serum magnesium concentrations be kept within the normal range.
REFERENCES
1. Koski G: Calcium salts are contraindicated in weaning of patients from cardiopulmonary bypass after coronary artery surgery. J Cardiothorac Anesth 2:570-575,1988 2. Vitez TS: Pro: Calcium salts are contraindicated in the weaning of patients from cardiopulmonary bypass. J Cardiothorac Anesth 2:567-569, 1988 3. Laban E, Charbon GA: Magnesium and cardiac arrhythmias. Nutrient or drug? J Am Co11Nutr 5:521-532,1986 4. Hollifield JW: Magnesium, depletion, diuretics, and arrhythmias. Am J Med 82:30-37,1987 (suppl3A) 5. Dyckner T: Serum magnesium in acute myocardial infarction. Acta Med Stand 207:59-66,198O 6. Ramee SR, White CJ, Svinarich JT, et al: Torsades de pointes and magnesium deficiency. Am Heart J 109:164-167,1985 7. Abraham AS, Rosenmann D, Kramer M, et al: Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch Intern Med 147:753-755,1987 8. Rasmussen HS, McNair P, Norregard, et al: Intravenous magnesium in acute myocardial infarction. Lancet 1:234-236, 1986 9. Friedman HS, Nguyen TN, Mokraoui AM, et al: Effects of magnesium chloride on cardiovascular hemodynamics in the neurally intact dog. J Pharmacol Exp Ther 243:126-130,1987 10. Hearse DJ, Steward DA, Braimbridge MV: Myocardial protection during ischemic cardiac arrest. J Thorac Cardiovasc Surg 75:877-885,197s 11. Foreman J, Pegg DE, Armitage WJ: Solutions for preservation of the heart at 0°C. J Thorac Cardiovasc Surg 89:867-871,1985 12. Cork RC, Gallo JA, Icenogle TB, et al: Effect of magnesium and calcium on myocardial function post-cardiopulmonary bypass. Anesth Analg 68:S60, 1989 13. Ryan MP: Diuretics and potassium/magnesium depletion. Am J Med 82:38-47, 1987 (suppl3A) 14. Chernow B, Banburger S, Stoiko M, et al: Hypomagnesemia in patients in postoperative intensive care. Chest 95:391-397, 1989 15. Chernow B, Roa J, Eguiguren L, et al: Unfilterable magnesium concentrations in critically ill children. Circ Shock 27:323-324, 1989 16. Abernathy MH, Fowler RT: Micellar improvement of the calmagite compleximetric measurement of magnesium in plasma. Clin Chem 28:520-522,1982 17. Nussbaum SR, Zahradnik R, La Vigne J, et al: Development of a highly sensitive two-site immunoradiometric assay for parathyroid hormone and its clinical utility in the evaluation of patients with hypercalcemia. Clin Chem 33:1364-1367,1987 18. Nussbaum SR, Thompson AR, Hutcheson KA, et al: Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery 104:1121-1127,1988 19. Borchgrevink PL, Oksendad AN, Jynge P: Acute extracellular magnesium deficiency and myocardial tolerance to ischemia. J Am Co11Nutr 6:125-130, 1987 20. Ferrari R, Albertini A, Curello S, et al: Myocardial recovery during post-ischemic reperfusion: Effect of nifedipine, calcium and magnesium. Mall Cell Cardiol 18:487-498,1986 21. Geffin GA, Love TF, Hendren WG, et al: The effects of calcium and magnesium in hyperkalemic cardioplegic solutions on myocardial preservation. J Thorac Cardiovasc Surg 98:239-250, 1989
22. Reynolds TR, Geffin GA, Titus JJ, et al: Myocardial preservation related to magnesium content of hyperkalemic cardioplegic solutions at 8°C. Ann Thorac Surg 47:907-913, 1989 23. Matsuda H: Open-state substructure of inwardly rectifying potassium channels revealed by magnesium block in guinea-pig heart cells. J Physiol (Lond) 397:237-258, 1988 24. Matsuda H, Saigusa A, Irisawa H: Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg”. Nature 325:156-159, 1987 25. Horie M, Irisawa H, Norma A: Voltage-dependent magnesium block of adenosinetriphosphate-sensitive potassium channel in guinea pig ventricular cells. J Physiol (Lond) 387:251-272, 1987 26. Horie M, Irisawa H: Rectification of muscarinic K+ current by magnesium ion in guinea pig atria1 cells. Am J Physiol253:H210H214,1987 27. Iseri LT, French JH: Magnesium: Nature’s physiologic calcium blocker. Am Heart J 108:188-193, 1984 28. Chiese M, Inesi G: Mg2’ and Mn*+ modulation of Ca2+ transport and ATPase activity in sacroplasmic reticulum vehicles. Arch Biochem Biophys 208:586-592,198l 29. Killen DA, Grogan EL II, Gower IE, et al: Effect of ACD blood prime on plasma calcium and magnesium. Ann Thorac Surg 13:371-380, 1972 30. Holden MP, Ionescu MI, Wooler GH: Magnesium in patients undergoing open-heart surgery. Thorax 27:212-218, 1972 31. Holden MP: Value of magnesium supplements during openheart surgery; a double-blind trial, in Naito HK (ed): Nutrition and Heart Disease. New York, NY, SP Medical and Scientific, 1982, pp 273-283 32. Zaloga GP, Chernow B, Cook D, et al: Assessment of calcium homeostasis in the critically ill surgical patient. Ann Surg 202:587-594, 1985 33. Wacker WEL, Parisi AF: Magnesium metabolism. N Engl J Med 278:658,1968 34. Lim P, Jacob E: Magnesium deficiency in patients on long-term diuretic therapy for heart failure. Br Med J 3:620-622, 1972 35. Kuller L, Farrier N, Caggiula A, et al: Relationship of diuretic therapy and serum magnesium levels among participants in the multiple risk factor intervention trial. Am J Epidemiol 122:1045-1059,1985 36. Johnson CJ, Peterson DR, Smith EK: Myocardial tissue concentrations of magnesium and potassium in men dying suddenly from ischemic heart disease. Am J Clin Nutr 32:967-970, 1979 37. Chipperheld B, Chipperfield JR: Heart-muscle magnesium, potassium, and zinc concentrations after sudden death from heart disease. Lancet 2:293-295,1973 38. Chipperfield B, Chipperheld JR: Differences in metal content of the heart muscle in death from ischemic heart disease. Am Heart J 95:732-737,1978 39. Elwood PC, Sweetnam PM, Beasley WH, et al: Magnesium and calcium in the myocardium: Cause of death and area differences. Lancet 2:720-722, 1980 40. Cohen L, Kirzes R: Magnesium sulfate and digitalis-toxic arrhythmias. JAMA 249:2808-2810, 1983 41. McCollister RJ, Flink EB, Lewis MD: Urinary excretion of
208
magnesium in man following the ingestion of alcohol. Am J Clin Nutr 12:415-420,1963 42. Sjorgren A, Floren CH, Nilsson A: Magnesium deficiency in IDDM related to level of glycosylated hemoglobin. Diabetes 35:459-463,1986 43. Levin GE, Mather HM, Polkington TRE: Tissue magnesium status in diabetes mellitus. Diabetologia 21:131-134, 1981 44. Fort P, Lifshitz F: Magnesium status in children with insulin-dependent diabetes mellitus. J Am Co11 Nutr 5:69-78, 1986 45. Zaloga GP, Chernow B: The multifactorial basis for hypocalcemia during sepsis. Ann Intern Med 107:36-41, 1987 46. Bone RC, Fisher CJ, Jr., Clemmer TP, et al: A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 317:653-658, 1987
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47. Marriott HJL: Practical Electrocardiography (ed 7). Baltimore, MD, Williams & Wilkins, 1983 48. Graeber GM: Creatine kinase (CK): Its use in the evaluation of perioperative myocardial infarction. Surg Clin North Am 65:539551,19x5 49. Forrester JS, Diamond G, Chatterjee K. et al: Medical therapy of acute myocardial infarction by application of hemodynamic subsets. N Engl J Med 295:1356-1362, 1404-1413, 1976 50. Killip T, Kimball JT: Treatment of myocardial infarction in a coronary care unit. Am J Cardiol20:457-464, 1967 51. Schrier RW, Conger JD: Acute renal failure: Pathogenesis, diagnosis, and management, in Schrier RW (ed): Renal and Electrolyte Disorders. Boston. MA, Little, Brown. 1980, pp 375 408
Hypomagnesemia Linda S. Aglio,
Is Common Following
Cardiac Surgery
MD, Gregory G. Stanford, MD, Rosemarie Maddi, MD, John L. Boyd Ill, MD, Samuel Nussbaum, MD, and Bart Chernow, MD, FACP
Hypomagnesemia is a common disorder in noncardiac surgical patients in the postoperative period, but the effect of cardiac surgery on serum magnesium concentrations remains unclear. The authors hypothesized that cardiac surgery is associated with hypomagnesemia, and prospectively studied 101 subjects (80 2 13.1 years of age) undergoing coronary artery revascularization (n = 70). valve replacement (n = 24), or both simultaneously (n = 7). Blood samples and clinical biochemical data were collected before induction of anesthesia, prior to cardiopulmonary bypass (CPB), immediately after CPB, and on postoperative day 1. Blood samples were analyzed for ultrafilterable magnesium, total magnesium, ionized calcium, parathyroid hormone, and free fatty
T
HE IMPORTANCE of the divalent cations calcium and magnesium in myocardial cell function has been known for decades, but the need for measurement and maintenance of extracellular concentrations of these ions in patients with cardiac disease remains controversial.‘,’ Calcium is frequently administered for its inotropic effect after cardiopulmonary bypass (CPB) even though the use of calcium salts for this indication has recently been challenged with arguments both for’ and against its use.L3 The role of magnesium in cardiovascular function has not been as extensively studied as the role of calcium, but its importance has been receiving increasing attention. Patients with a magnesium deficiency have an increased incidence of supraventricular and ventricular dysrhythmias,4a5and magnesium salts are now the recommended treatment for a particularly troublesome ventricular dysrhythmia, torsade de pointes.6 Patients with hypomagnesemia have a higher incidence of potentially lethal dysrhythmias following myocardial infarction (MI) than patients with a normal serum magnesium concentration.’ Magnesium infusions in patients following MI decrease potentially lethal dysrhythmias’,’ and decrease mortality.* Magnesium infusions in dogs lower heart rate, decrease cardiac contractility and coronary blood flow, and markedly decrease myocardial oxygen consumption and myocardial oxygen extraction.9 The effect of CPB on magnesium balance is not known. Magnesium administered during CPB may decrease calcium influx through calcium channels and in so doing may potentiate potassium cardioplegia during cardiac surgery.‘0-‘2 In the isolated rat heart, magnesium displays a marked dose-dependent protective effect on ischemic myocardium.” Magnesium use in the pump prime (instead of calcium) significantly improves myocardial performance when compared with a pump prime using calcium.”
acid concentrations. Outcome variables were also determined. Eighteen of gg (18.2%) subjects had hypomagnesemia preinduction and this number increased to 71 of 100 (71.0%) following cessation of CPB (P < 0.05). Patients with postoperative hypomagnesemia had a higher frequency of atrial dysrhythmias (22 of 71 [31.0%] v 3 of 29 [10.3%], P < 0.05) and required prolonged mechanical ventilatory support (22 of 83 [34.g%] v 4 of 33 [12.1%], P < 0.05). Hypomagnesemia is common following cardiac surgical procedures with CPB and is associated with clinically important postoperative morbidity. Copyright 0 1991 by W. 6. Saunders Company
Because patients undergoing CPB may be at increased risk of hypomagnesemia and because these patients may not tolerate hypomagnesemia as well as other critically ill patients, it was hypothesized that hypomagnesemia is a frequent occurrence in cardiac patients. To test this hypothesis, magnesium homeostasis was prospectively studied in a large group of cardiac surgical patients. The authors have previously described clinically important hypomagnesemia in critically ill adultI and pediatric patients.” In this report, those studies have been extended to another group of critically ill patients: those patients recovering from cardiac surgery involving CPB. MATERIALS
AND METHODS
Patients over the age of 18 years electively scheduled for cardiac surgery that would require CPB were invited to participate in the
This article is accompanied by an editorial. Please see: Finlayson DC: Magnesium: Its time has come. J Cardiothorat Vast Anesth 5:199-200,199l
From the Department of Anesthesia, Brigham and Women S Hospital/Harvard Medical School, and the Departments of Anesthesia and Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA. Supported in part by funds from the Hemy IL Beecher Memorial Anesthesia Research Laboratories of the Massachusetts General Hospital, Boston, MA. Address reprint requests to Linda S. Aglio, MD, Depatiment of Anesthesia, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02114. Copyright o 1991 by W B. Saunders Company 1053-0770/91/0503-0002$03.00/0
AGLIO ET AL
202
study. The study was approved by the Institutional Review Board at the study hospital, and all patients signed written informed consent. Following admission to the study, a complete history was recorded with particular attention to predisposing illnesses and drugs known to affect magnesium metabolism. Patients were then followed by study personnel throughout their hospitalization, and all complications and adverse reactions were carefully monitored and recorded. Particular attention was paid to those complications that could be related to magnesium dyshomeostasis including postoperative dysrhythmias, MI, congestive heart failure, respiratory failure, excessive potassium requirements, hypocalcemia, sepsis, and death. These complications were determined using standard definitions (Table 1). Table 1. Criteria for Complications Sepsis?
Patients who meet the following criteria are classified
as having a septic episode Clinical evidence of infection Fever
(> 38.3”C
rectal) or hypothermia
Tachycardia (>90
(< 35.6”C
rectal)
beats/min)
Tachypnea (>20 breathdmin while breathing spontaneously) At least one of the following manifestations of inadequate organ perfusion or organ dysfunction Altered mentation (in relation to patient’s baseline) Hypoxemia (arterial oxygen tension the
upper limit of normal for the labo-
ratory performing the assay) Oliguria (output ~30 mL or 0.5 mUkg for at least 1 hour) Myocardial Infarction4’,48: Patients having any of the following criteria are considered as having an acute myocardial infarction Classic electrocardiogram
changes including
The fresh appearance of Q waves or the increased prominence of preexisting ones ST segment elevation T wave inversions Serum CK-MB bands in excess of 5% of the serum total CK
Blood samples were collected from each patient at four time points. The first sample was obtained preoperatively before the induction of anesthesia (time 1). The second sample was obtained after the induction of anesthesia and after the skin incision had been made, but before the initiation of CPB (time 2). The third sample was collected after the completion of CPB (time 3). The fourth sample was collected on the morning of postoperative day I (time 4). Blood samples were immediately placed on ice, and the serum was separated and stored at -70°C until the assays were performed. The serum ionized calcium concentration was measured using an ion-specific selective electrode (Nova II, Nova Biomedical, Waltham, MA). The serum total magnesium concentration was measured using a specific spectrophotometric assay.‘” The normal serum total magnesium using this assay is 0.8 to 1.2 mmol/L (1.6 to 2.0 mEq/L). The serum ultrafilterable magnesium concentration was measured by placing 750 FL of serum into an Amicon Centifree micropartition filter system (Amicon Division, W.R. Grace and Co. Danvers, MA) followed by centrifugation at 3,000~ using a fixed-angle centrifuge. The protein-free filtrate was assayed for magnesium concentration using the same spectrophotometric assay as was used for the serum total magnesium concentration. The normal serum ultrafilterable magnesium concentration using this assay is 0.44 to 0.66 mmol/L (0.88 to 1.32 mEq/L). The serum parathyroid hormone (PTH) concentrations were measured using a specific and sensitive two-site immunoradiometric assay that detects the intact PTH molecule“ (Allegro, Intact PTH l-84, Nichols Institute Diagnostics, San Juan Capistrano, CA). This assay uses two affinity-purified polyclonal antibodies to quantitate accurately only the intact, circulating hormone. It has been found to be specific under conditions of a changing PTH concentration.” Serum free fatty acid concentrations were measured using an enzymatic assay (NEFA C. Wako Pure Chemical Industries, Ltd. Osaka, Japan). Serum potassium concentrations were measured using an automated analyzer. Statistical analysis of discrete variables was performed using x’ analysis and Fisher’s exact test. Continuous variables were analyzed using an analysis of variance for repeated measures over time. A P value less than 0.05 was considered to be statistically significant. Unless otherwise noted, data are expressed as mean ? SD.
or greater than 50 IU/L in the first 30 hours after surgery Serum LDHJLDH, greater than 1 .OOon two separate samples
RESULTS
24 to 48 hours after surgery Dysrhythmias4’
Overall Patient Population
Supraventricular: Disturbances of rhythm originating in the atrium or atrioventricular junction characterized by normal QRS complexes unless complicated by aberrant ventricular conduction Ventricular: Disturbances of rhythm originating in the ventricles associated with bizarre QRST complexes with prolonged QRS intervals. Heart Failure4’?
Patients with the following criteria are desig-
nated as having diminished cardiac function Pulmonary artery wedge pressure > 18 mm Hg Cardiac index < 2.2 L/min/m2 Acute Renal Failure”: Patients who have a serum creatinine > 2.5 mg/dL with previously normal renal function or an increase in the serum creatinine >2.0 mg/dL in the presence of chronic renal insufficiency and who meet one of the following criteria are designated as having acute renal failure Urine output ~30 mL/h with an adequate intravascular volume and in the absence of obstruction Urine osmolality 2.0 (RF1 = U/P Na divided by U/P creatinine x 100)
A total of 101 patients were entered into the study. The mean age of the study population was 60.4 t 13.1 years (range, 22 to 84 years). There were 82 men and 19 women. Seventy patients underwent coronary artery bypass grafting (CABG), 24 patients underwent either aortic or mitral valve replacement, and 7 patients had combined CABG and valve replacement. Twelve patients had undergone previous cardiac surgery, but none of these operations occurred within the 12 months prior to this study. A summary of the complications is shown in Table 2. The most common postoperative complications were dysrhythmias, which occurred within 24 hours of surgery in 49 of 101 (48.5%) patients. Twenty-three of 101 (22.8%) patients developed atria1 dysrhythmias only, 23 of 101 (22.8%) patients developed ventricular dysrhythmias only, and 3 of 101 (3.0%) patients developed both atria1 and ventricular dysrhythmias. Respiratory failure defined as the requirement for mechanical ventilation longer than 24 hours after
HYPOMAGNESEMIA
203
FOLLOWING CARDIAC SURGERY
Table 2. Comparison of Complications Between Patients With Normal and Low Total Serum Magnesium Concentrations Time 4
Time 3
Complication
at Times 3 and 4
No. With
No. With
No. With
Low Mg++
Normal Mg++
Low Mg++
Normal Mgtt
29/100 (29.0%)
63/96* (65.6%)
33/96 (34.4%)
No. With
Total patients
71/100*
Atrial dysrhythmias
22171 ?? (31.0%)
3/29
(10.3%)
18/63
(28.6%)
El33 (24.2%)
Ventricular dysrhythmias
19171
(26.8%)
7/29
(24.1%)
16/63
(25.4%)
10/33 (30.3%)
Congestive heart failure
7/71
(9.8%)
4/29
(13.8%)
El63
(12.7%)
3/33 (9.1%)
Sepsis
7/71
(9.8%)
l/29
(3.4%)
6/63
(9.5%)
21171
(29.6%)
5/29
(17.2%)
Death
a/71
(11.3%)
5/29
(17.2%)
3/63
(4.8%)
Hypocalcemia
5/71
(7.0%)
2/29
(6.9%)
14/63
(22.2%)
6/33 (18.2%)
34171
(47.9%)
16/29
(55.2%)
43/63
(68.2%)
24133 (72.7%)
51171
(71.8%)
22/29
(75.9%)
46/63
(73.0%)
28/33 (84.8%)
Ventilatory support > 24 h
Increased free fatty acids
(71 .O%)
22/63* (34.9%)
2/33 (6.1%) 4/33 (12.1%) 6/33 (18.2%)
Required > 100 mEq K’ over postoperative day 1 ?? P < 0.05 when comparing the hypomagnesemic
patients with the normomagnesemic
surgery was also common. Eleven of 101 (10.9%) patients developed congestive heart failure and 10 of 101 (9.9%) patients had postoperative MIS. Thirteen of the 101 patients died during the study period. Other complications included a cerebrovascular accident in one patient and a postoperative small bowel obstruction requiring reoperation in another patient. Nine patients developed the sepsis syndrome, but only one of these patients died. One patient with chronic renal failure developed acute renal failure postoperatively. Serum Total Magnesium (Hypomagnesemic v Normomagnesemic Patients)
Blood samples were not available for a small number of patients at all time points because of mortality, and because, on occasion, an insufficient sample for the magnesium or ultrafilterable magnesium assays remained after other laboratory tests had been performed. Nineteen of 99 (19.2%) patients had serum total hypomagnesemia prior to the induction of anesthesia (Fig 1). This number increased to 31 of 98 (31.6%) patients after the induction of anesthesia and surgery, but prior to CPB; this increase was not statistically significant. A significantly greater number of patients were hypomagnesemic after CPB (71/100 patients, 71%) when compared with the number of hypomagnesemic tota!pati.9nfs=lOl-
Fig 1. Numbers of patients with serum total ??and ultrafilterable 0 hypomagnesemia at each time point in the study. Time 1, baseline immediately prior to surgery; time 2, after the beginning of surgery but before CPB; time 3, after completion of CPB; time 4, postoperative day 1. ?? P 5 0.05 compared with baseline.
patients at the same time point.
patients preoperatively (P < 0.05). The number of hypomagnesemic patients remained significantly increased into postoperative day 1 (63/96 patients, 65.6%; P < 0.05). A comparison of the complications in the hypomagnesemic group (those patients with total serum magnesium concentrations less than 0.8 mmol/L at time 3 and/or time 4) versus the normomagnesemic group is shown in Table 2. A significantly greater number of patients who were hypomagnesemic at time 3 had atria1 dysrhythmias in the postoperative period (P < 0.05). Hypomagnesemia was not more common in patients with ventricular dysrhythmias. Those patients whose hypomagnesemia persisted into postoperative day 1 required prolonged ventiiatory support (mechanical ventilation longer than 24 hours after surgery). Patients who developed congestive heart failure postoperatively had a higher frequency of hypomagnesemia at time 2 (P < 0.05), but not at either time 3 or time 4. Hypomagnesemia was not associated with increased free fatty acid concentrations or hypocalcemia. Although the need for large amounts of potassium supplementation was common in this patient population, it was not significantly associated with hypomagnesemia. Hypomagnesemia was not more common in those patients who died, and none of these deaths could be directly attributed to complications related to hypomagnesemia. A comparison of risk factors for hypomagnesemia is provided in Table 3. A significantly greater number of patients receiving chronic digoxin therapy were hypomagnesemic preoperatively (P < 0.05), but this difference did not persist throughout the study. Patients taking diuretics did not have a higher prevalence of hypomagnesemia preoperatively; however, this group did have a higher incidence of serum total hypomagnesemia at time 3 (P < 0.05). When the type of diuretic was analyzed, neither loop diuretics nor thiazide diuretics could be implicated as the cause of this hypomagnesemia after CPB. Patients who were receiving calcium antagonists preoperatively had a lower prevalence of hypomagnesemia at time 3, suggesting that these agents may in some way prevent the loss or redistribution of magnesium during CPB. A significantly higher number of diabetic patients were hypomagnesemic at the beginning of the study (P < 0.05).
AGLIO ETAL
204
Table 3. Comparison of Risk Factors for Hypomagnesemia
Between Patients With Normal and Low Total Serum Magnesium Concentrations
Time 1
Time 2
Time 3
Time 4 _-
No. With Risk Factor
Totalpatients
Low Mg+’
No. With Normal Mg
No. With
’
Low Mg+ +
No. With
Mg*
Normal
No. With
No. With
No. With
Low Mg’
Normal Mg
Low Mg’
No. Wtth
’
Normal Mg’
’
19/99 (19.2%) 80/99 (80.8%) 31198 (31.6%) 67/98 (68.4%) 711100 (71.0%) 291100 (29.0%) 63/96 (65.6%) 33196 (34.4%)
Diuretics All
5/19 (26.3%) 28/80 (35.0%) IO/31(32.2%) 23167 (34.3%) 28/71* (39.4%) 5/29 (17.2%) 21/63 (33.3%) 9/33 (27.3%)
Loop diuretics
5/19 (26/3%) 24/80(30.0%) 8/31 (25.8%) 21/67 (31.3%) 25171 (35.2%) 4129 (13.8%) 18/63(28.6%) 8/33 (24.2%)
Thiazidediuretics
2/19 (10.5%) 11/80(13.8%) 4/31 (12.9%) 9/67 (13.4%) 11/71 (15.5%) 2/29 (6.9%)
Calcium antagonists Digoxin
6/63 (9.5%)
4/33 (12.1%)
14/19 (73.7%) 49/80 (61.2%) 20/31 (64.5%) 41/67 (61.2%) 40/71* (56.3%) 24129 (82.8%) 45/63 (71.4%) 18/33(54.5%) 7/19* (36.8%) 13/80(16.3%) 6/31 (19.4%) 13/67(19.4%) 17171 (23.9%) 4/29 (13.8%) 13/63 (20.6%) 7/33 (21.2%)
Diabetesmellitus All
7/19* (36.8%) 12/80(15.0%) 5/31 (16.1%) 13167 (19.4%) 13/71 (18.3%) 6/29 (20.7%) 12/63(19.0%) 7/33 (21.2%)
Insulin-dependent
l/19 (5.3%)
2/80 (2.5%)
l/31(3.2%)
l/67(1.5%)
2/71 (2.8%)
1129 (3.4%)
2/63 (3.2%)
l/33(3.0%)
Noninsulin-dependent 6/19* (31.6%) lo/80 (12.5%) 4/31 (12.9%) 12/67 (17.9%) 11171 (15.5%) 5/29 (17.2%) lo/63(15.9%) 6/33 (18.8%)
?? P 5 0.05when comparing the hypomagnesemic patients with the normomagnesemic patients at the same time point.
However, this difference was present only at time 1, and the diabetic patients did not have an increased incidence of hypomagnesemia either at the conclusion of CPB or on postoperative day 1. The diabetic population was separated into insulin-dependent and noninsulin-dependent subsets and separately analyzed; only three patients had insulindependent diabetes, so statistical comparisons between the two groups were not meaningful.
terable hypomagnesemia at time 4 (P < 0.05), whereas there was no difference in those patients receiving thiazide diuretics. In contrast to the serum total magnesium, calcium channel antagonists had no effect on the serum ultrafilterable magnesium concentration. Similarly, diabetics and nondiabetics had similar ultrafilterable magnesium concentrations. DISCUSSION
Serum UltrafilterableMagnesium (Hypomagnesemic v Normomagnesemic Patients)
The serum ultrafilterable magnesium concentration was measured in order to determine if this variable was a better predictor of complications in cardiac surgical patients. Several samples could not be analyzed because insufficient serum was available after the ionized calcium and serum total magnesium concentrations had been obtained. There were a number of patients with decreased serum ultrafilterable magnesium concentration at times 1, 2, and 3; however, there were more patients with ultrafilterable hypomagnesemia at time 4 than patients with total hypomagnesemia. There was no correlation between the serum ultrafilterable magnesium concentration and the serum total magnesium concentration (Fig 2). A comparison of complications in patients with low and normal serum ultrafilterable magnesium concentrations is shown in Table 4. The significant finding was that patients with a low serum ultrafilterable magnesium concentration required large amounts of intravenous potassium ( > 100 mEq) in order to correct hypokalemia compared with those patients with normal ultrafilterable magnesium concentrations (P < 0.05). Patients with low ultrafilterable concentrations did not experience an increased incidence of atria1 dysrhythmias or prolonged ventilatory support compared with patients with normal ultrafilterable magnesium concentrations. The risk factors for the development of ultrafilterable hypomagnesemia are analyzed individually in Table 5. There were no statistical differences between the numbers of patients with normal and low ultrafilterable magnesium concentrations at any time point in patients taking diuretics. When the individual diuretic classes were examined, patients on loop diuretics had a lower incidence of ultrafil-
Magnesium is an important intracellular ion involved in numerous enzymatic and biochemical reactions. The heart requires magnesium for both pump function and proper action potential transmission. Cardiac surgery with CPB often involves an ischemic period to the myocardial cells. The effect of this ischemia and cellular hypoxia is lessened by hypothermia, but still results in impairment of cellular energy utilization. Following CPB, the recovery of myocardial cell function is dependent on the restoration of oxidative metabolism. Magnesium is an absolute require-
z
k
1.0
E”0.8
g $
0.6
Z % Z
0.4
= E
0.2
I
0.0 0.0
0.5
1 .o
1.5
2.0
2.5
Total Mg (mmol/L) Fig 2. A comparison of simultaneous total magnesium concentration and ultrafilterable magnesium concentration assayed on all serum samples obtained during the study. Least squares regression analysis demonstrated no correlation between the two values: y = 0.16x + 0.37; r’ = 0.16.
HYPOMAGNESEMIA
205
FOLLOWING CARDIAC SURGERY
Table 4. Comparison of Complications Between Patients With Normal and Low Ultrafilterable
Serum Magnesium Concentrations
at
Times 3 and 4 Time 3 No. With Low Mg++
Complication
Time 4 No. With Normal Mg++
No. With Low Mg++
No. With Normal Mg++
Total patients
49/98 (50.0%)
49/98 (50.0%)
64187
(73.6%)
23187 (26.4%)
Atrial dysrhythmias
13/49 (26.5%)
12/49 (24.5%)
18164 (28.1%)
5123 (21.7%)
Ventricular dysrhythmias
9/49 (18.4%)
17149 (34.7%)
17164 (26.6%)
8123 (34.8%)
Congestive heart failure
6/49 (12.2%)
3/49 (6.1%)
7164 (10.9%)
l/23 (4.3%)
Sepsis
6/49 (12.2%)
l/49 (2.0%)
6164
14/49 (28.6%)
11/49 (22.4%)
Ventilatory support > 24 h
20/64
(9.4%)
l/23 (4.3%)
(31.2%)
5/23 (12.7%)
Death
4/49 (8.2%)
9/49 (18.4%)
3164 (4.7%)
Hypocalcemia
3/49 (6.1%)
4149 (8.4%)
12164 (18.8%)
27/49 (55.1%)
23/49 (46.9%)
49164
(76.6%)
18123 (78.3%)
37149 (75.5%)
34/49 (69.4%)
53/64* (82.8%)
13/23 (56.5%)
Increased free fatty acids
6/23 (26.4%) 4/23 (17.4%)
Required > 100 mEq K’ over postoperative day 1 *P < 0.05 when comparing the hypomagnesemic
patients with the normomagnesemic
ment of oxidative phosphorylation, and magnesium depletion may contribute to depletion of adenosine triphosphate (ATP) during relative hypoxia.‘9.20Magnesium has a protective role in experimental ischemia in isolated organ studies, and an increased magnesium concentration in the buffer maintains cellular ATP stores.19~2’~22 In humans, the addition of magnesium to the cardioplegia solution during cardiac surgery enhances recovery from the ischemic hypothermic arrest at the completion of surgery.‘* Magnesium may exert its cardiac effects through its influence on potassium and calcium channels. Several types of potassium channels allow potassium to pass more readily into the cell than out of the cell in a process called inward rectification.*’ This inward rectification may be caused by intracellular magnesium blocking the efflux of potassium from the ce11.*4~26 When the intracellular magnesium is depleted, the potassium channel loses its selectivity, and potassium can pass equally well into the cell as well as out of the cell. The intracellular magnesium may then act as a regulator of depolarization and repolarization, and alterations in magnesium concentrations would cause derangements in the propagation of action potentials leading to dysrhythmias. Table 5. Comparison of Risk Factors for Hypomagnesemia
patients at the same time point.
Magnesium may also function as a physiological calcium antagonist.*’ Intracellular calcium is normally sequestered in the sarcoplasmic reticulum and is released into the cytoplasm during cellular activation. The cell returns to the resting state by active calcium uptake of the sarcoplasmic reticulum as well as extrusion of calcium from the cell. The uptake of calcium by the sarcoplasmic reticulum is highly magnesium-dependent and is stimulated at low magnesium concentrations and inhibited by increasing intracellular magnesium.Z8 Because this sarcoplasmic uptake is a primary mechanism of regulating intracellular calcium, even minor changes in the intracellular magnesium concentrations will profoundly affect calcium fluxes and cardiac function. These altered calcium fluxes may explain the increased atria1 dysrhythmias observed in the hypomagnesemic patients in the early postoperative period (during the first 24 hours after surgery). Interestingly, hypomagnesemia is significantly associated with these dysrhythmias immediately after surgery and not on the first postoperative day. However, most atria1 dysrhythmias occur early after surgery with a decreasing incidence as the time from surgery increases. This clinical observation suggests that hypomagnesemia may act as a cofactor in the induction of these
Between Patients With Normal and Low Ultrafilterable
Serum Magnesium
Concentrations Time 1 RiskFactor Total patients
Time 2
Time 3 No. With Low Mg+’
No. With Normal Mg++
Time 4
With Low Mg++
No. With Normal Mg++
No. With Low Mg++
No. With Normal Mg++
14/92 (15.2%)
78/92 (84.8%)
22/92 (23.9%)
70/92 (76.1%)
49/98 (50.0%)
49/98 (50.0%)
64/87 (73.6%)
23/87
No.
No. With Low Mg++
No. With Normal Mg++ (26.4%)
Diuretics All
3/14 (21.4%)
29/78 (37.2%)
4/22 (18.2%)
28/70 (49.0%)
13/49 (26.5%)
20/49 (40.8%)
18/64 (28.1%)
12/23* (52.2%)
Loop diuretics
3/14 (21.4%)
25/78 (32.0%)
4/22 (18.2%)
24/70 (34.3%)
11/49 (22.4%)
18/49 (36.7%)
14/64 (21.9%)
12/23* (52.2%)
Thiazide diuretics
O/14 (0.0%)
12/78 (15.4%)
l/22 (4.5%)
11/70 (15.7%)
4/49 (8.2%)
9/49 (18.4%)
6/64 (9.4%)
5/23
(21.7%)
lo/14 (71.4%)
49/78 (62.8%)
13/22 (59.1%)
45/70 (64.3%)
35/49 (71.4%)
27/49 (55.1%)
43/64 (67.2%)
12/23
(52.2%)
4/14 (28.6%)
15/78 (19.2%)
5/22 (22.7%)
14/70 (20.0%)
lo/49 (20.4%)
11/49 (22.4%)
14/64 (21.9%)
6/23
(26.1%)
All
2/14 (14.3%)
13/78 (16.7%)
5/22 (22.7%)
13/70 (18.6%)
lo/49 (20.4%)
7/49 (14.3%)
12/64 (18.8%)
Insulin-dependent Noninsulin-dependent
l/14 (7.1%)
l/78 (I .3%)
2/22 (9.1%)
l/70 (1.4%)
2/49 (4.1%)
o/49 (0.0%)
2/64(3.1%)
3/23 O/23
(13.0%) (0.0%)
12/78 (15.4%)
3/22 (13.6%)
12/70 (17.1%)
8/49 (16.3%)
7149 (14.3%)
lo/64 (15.6%)
3/23
(13.0%)
Calcium antagonists Digoxin Diabetes mellitus
l/l4
(7.1%)
?? P 5 0.05 when comparing the hypomagnesemic
patients with the normomagnesemic
patients at the same time point.
AGLIO ET AL
rhythm disturbances. The other factors that may contribute to dysrhythmia induction include volume overload, hypovolemia, pH changes, and postcardiotomy irritability. Because the patient stabilizes over the early postoperative period and the presence of these cofactors disappears, it is speculated that hypomagnesemia has less of an effect on the myocardial conduction system. Magnesium concentrations have been measured in previous studies involving CPB. Killen et alZ9 measured total magnesium concentrations in 38 patients who received acid-citrate-dextrose (ACD) as a blood preservative in the pump prime. In that study, there was a marked depression of the plasma magnesium concentration that could be prevented by the addition of 10% magnesium sulfate in the amount of 3 mL/U of ACD blood returned to the patient. Postoperative complications were not mentioned. Holden et al”’ measured total magnesium concentrations in the serum of patients before and after cardiac and noncardiac thoracic surgery. Urine magnesium concentrations were also measured. Baseline serum magnesium concentrations were low in patients who had recently been in congestive heart failure. All patients had hypomagnesemia postoperatively, but those patients undergoing CPB had lower magnesium concentrations, which remained decreased for 3 postoperative days. Urine magnesium concentrations increased during CPB, but then decreased in the immediate postoperative period and remained decreased for the first 2 postoperative days. No definite relationship could be demonstrated between hypomagnesemia and postoperative complications. In a subsequent study, Holden” randomized patients to receive magnesium sulfate or a placebo after valve replacement surgery. The treatment group normalized their serum magnesium concentrations whereas the placebo group remained hypomagnesemic. The treatment group had fewer complications related to pacing difficulties, dysrhythmias, mental derangements, and peripheral neurological problems. There were no significant differences with respect to postoperative bleeding or urinary output between the two groups. Although this study involved a small number of patients, it was the first to show a beneficial effect of magnesium supplementation after cardiac surgery. In the present study, an association was found between hypomagnesemia and complications after cardiac surgery involving CPB. In addition, this study is the first to measure ultrafilterable magnesium concentrations in cardiac surgical patients. Because these patients have fluid shifts and rapid changes in plasma protein concentrations, the ultrafilterable magnesium concentration may be a more reliable measurement of the available magnesium. As has been found in previous studies comparing ionized calcium with total calcium concentration,” the ultrafilterable magnesium concentration was abnormal much less often than the total magnesium concentration in the study patients. Because at present there is no reliable means of measuring the ionized magnesium concentration, the ultrafilterable magnesium
concentration remains the closest approximation to the biologically active ionized magnesium concentration. The finding of such a high prevalence of hypomagnesemia after CPB (711100 patients) was surprising. Previous studies of serum total magnesium concentration in postoperative patients admitted to the intensive care unit found an incidence of 60%.” In the pediatric population, about 30% of critically ill children have hypomagnesemia.” The only previous operation found to be associated with postoperative hypomagnesemia is esophagogastrectomy. Cardiac surgical patients are a group that would be expected to have a high prevalence of hypomagnesemia because of the frequent use of drugs that adversely affect magnesium balance. The kidney is responsible for maintaining an adequate serum magnesium concentration, and about 65% of the magnesium filtered at the glomerulus is reabsorbed in the loop of Henle.” Not surprisingly, loop diuretics interfere with this reabsorption, causing clinically important renal losses of magnesium.i.‘4 Thiazide diuretics can also induce hypomagnesemia when used chronically.‘S’i In this study, 21 of 101 patients were receiving loop diuretics preoperatively. 5 patients received thiazide diuretics preoperatively, and 8 patients were receiving both types of diuretics. Baseline hypomagnesemia was not found to be more prevalent in the patients receiving these medications than in patients who were not receiving diuretics. However, the serum magncsium concentration may not adequately reflect the intracellular magnesium concentration. Other investigators have found lower magnesium concentrations in the heart muscle of patients after sudden coronary deaths when compared with trauma-related deaths.“-“’ which did not correlate with the serum magnesium concentration. The present patients may have had a decreased intracellular magnesium concentration that became clinically important after the stress of cardiac surgery. Another drug used commonly in cardiac surgical patients, digoxin. interferes with magnesium homeostasis by causing an increased efflux of magnesium from the cell through its action on Ca-Mg ATPase.“’ Hypomagnesemia can accentuate digitalis toxicity, and magnesium salts have been used successfully to treat digitalis toxicity.“’ Alcohol is used commonly in this society and results in increases in renal magnesium losses that can lead to chronic magnesium depletion.“’ Some cardiac surgical patients also may have associated illnesses that alter magnesium homeostasis. Patients with type I diabetes mellitus arc consistently hypomagnesemic,4’~1J which correlates inversely with the degree of control of hyperglycemia.” The cause of hypomagnesemia after cardiac surgery is unknown; however, as with hypocalcemia in critically ill patients? it is speculated that the cause of hypomagnesemia is probably multifactorial. The presence of hypomagnesemia after cardiac surgery may be a laboratory curiosity, but the authors believe that it is not the case. Future research should be directed at determining if correction of hypomagnesemia will decrease the incidence of postoperative complications. Previous work by Holden” suggests that correction of hypomagnesemia after cardiac surgery leads
HYPOMAGNESEMIA
FOLLOWING
CARDIAC
SURGERY
207
to decreased number and severity of complications. Magnesium decreases dysrhythmias after MI,’ which suggests that it may be beneficial after other ischemic insults. A study to investigate the use of exogenous magnesium therapy after
cardiac surgery is currently in progress. At the present, it is recommended that serum magnesium concentrations be followed closely after cardiac surgery and that serum magnesium concentrations be kept within the normal range.
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