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Digitalis toxicity and hypomagnesemia
Experimental
and laboratory
Digitalis
toxicity
reports
and
hypomagnesemia
Robert H. Seller, M.D. Jose Cangiano, M.D. Kwan E. Kim, M.D. Saul Mendelssohn, M.D. Albert N. Brest, M.D. Charles Swartz, M.D. Philadelphia, Pa.
I
n a prior study,’ we observed that serum magnesium levels were significantly lower in 13 digitalized patients with congestive heart failure (1.40 mEq. per liter [mEq./L.]) than in 72 control subjects (1.93 mEq./L.) Jackson and Meier2 noted an excessive prevalence of hypomagnesemia in patients on diuretic drugs. We found frank hypomagnesemia in four patients with digitalis toxicity. These observations, coupled with the fact that magnesium deficiency leads to an intracellular deficit of potassium,3*4 suggested that hypomagnesemia contributes to the development of digitalis toxicity. While some investigators have shown that the induction of hypomagnesemia (by feeding growing puppies a diet deficient in magnesium) facilitates the development of digitalis toxicity,5*6 others were unable to confirm this finding. Kleiger and associates7 observed that the arrhythmia produced by acetylstrophanthidin persisted longer in From the Section of Nephrology and Vascular This study was supported by funds from the No. HE 08052). and the Heart Association The statistical and computational portion of Center which is supported by the Special 00266). Received for publication Jan. 20, 1969. Reprint requests to: Dr. Seller, Department St., Philadelphia, Pa.
Vol.
79, No.
1, pp. 57-68
January,
1970
hypomagnesemic than in normal dogs. Kim and co-workers8 observed a small but significant rise in serum magnesium concentration in patients subsequent to the dissipation of digitoxic arrhythmias. In most studies utilizing parenteral magnesium salts in the treatment of digitalis toxicity, they were given empirically without determining plasma magnesium concentrations.97’0 The resultant transient antiarrhythmic activity of magnesium salts may be analogous to the administration of potassium to normokalemic patients with digitalis toxicity. In these instances, potassium salts often have limited usefulness and may further depress atrioventricular conduction. In contrast, potassium salts are particularly effective when digitalis toxicity is associated with hypokalemia. The purpose of this investigation was twofold: (1) to determine whether hypomagnesemia facilitates the development of digitalis toxicity; and (2) to determine the
Diseases, Hahnemann Medical College and Hospital, Philadelphia, Pa. United States Public Health Service, the National Heart Institute (Grant of Southeastern Pennsylvania. this study was performed at the Hahnemann Medical College Computer Resources Branch of the National Institutes of Health (Grant No. FR-
of Medicine,
Hahnemann
Medical
College
American
and
Hospital,
230 N. Broad
Heart Journal
57
5r ! *Beam
Bolonce
Intro-orteriol blood pressure monitoring
Infusion pump v-Acetylstrophonthidin
Mg’t + Free Diolyrote Fig.
1. Schematic
drawing
of animal
experiment
efficacy of intravenously administered magnesium sulfate in the treatment of digitalis toxicity associated with hypomagnesemia. Methods
and
materials
Studies were performed in 19 adult mongrel dogs whose average weight was 20 kilograms. Anesthesia was induced by 25 mg. per kilogram of intravenous Pentothal Sodium and additional doses were given as needed to maintain anesthesia. The dogs were ventilated through a cuffed endotracheal tube with a Harvard respirator whose tidal volume and rate were adjusted to dog weight. The dogs were hydrated with 300 C.C. of isotonic saline. A two-layer Kiil kidney hemodialysis, primed with 300 C.C. of normal saline, was started using femoral arterial and venous cannulations. Magnesium-free deionized water was used for the dialysate bath. The following substances were added to 100 liters of deionized water: NaCl, 620 Gm. ; NaHC03, 300 Gm.; KCl, 30 Gm.; MgC12, 12 Gm.; CaC12, 22 Gm.; lactic acid, 40 c.c.; and glucose, 100 Gm. This resulted in cation concentrations which approximated the
ionized iraction found in normal r;LliiIic. plasma: Sa, 141 mEq./L.; K, 4.0 mEq./L.; Mg, 1.3 mEq.,/‘L.; Ca, 3.0 mEq.jL.; (Jl, 116 mEq./L.; and HCOI, 35 mEq./L. During dialysis the dog’s weight was continuously monitored on a beam balance, and isotonic saline replacement I\-as given in order to maintain a constant weight. Continuous intraarterial blood pressure was determined with a strain-gauge transducer and monitored on an oscilloscope. Serial Lead II electrocardiograms were obtained with a direct-writing electrocardiograph (Fig. 1). Acetyl strophanthidin \vas infused through an indwelling venous catheter at a rate of 100 pg per minute by means of a constant infusion pump. The infusion was continued until the onset of digitalis toxicity, as evidenced by A-V dissociation, nodal tachycardia, or ventricular tachycardia. All dogs were dialyzed with a normal bath as well as a bath identical in composition but free of magnesium. Three groups of animals were studied (Fig. 2). Groz~p I. Eight dogs had infusions of acetyl strophanthidin after fs, 3j5, and 656 hours of dialysis with a normal bath. The fourth acetyl strophanthidin infusion was performed after 3 additional hours of dialysis utilizing the magnesium-free dialysate. Group II. Eight dogs had infusions of acetyl strophanthidin after ?,s and 355 hours of dialysis with a normal bath. The third and fourth acetyl strophanthidin infusions were performed after 3 and 6 additional hours of dialysis with the magnesium-free dialysate. Group III. In order to assure that there was no cumulative effect due to repeated digitalization, the experiment was reversed. Three dogs had acetyl strophanthidin infusions performed at M, 35$, and 655 hours of dialysis with a magnesiumfree bath. Then 4 C.C. of a 25 per cent magnesium sulfate solution was injected intravenously to correct the hypomagnesemia and terminate the arrhythmia. The fourth acetyl strophanthidin infusion was performed after 3 additional hours of dialysis with a normal bath. In order to determine the efficacy of magnesium sulfate in the treatment of
VollLmc Nlcmber
79
Digitalis
1
toxicity and hypomagnesemia
59
GROUP I (8 DOGS)
GROUP II (8 DOGS)
GROUP III (3 DOGS)
0 ‘+
I
2
3
Dialysis
4
with
5 HOURS
magnesium
6
7
free
8
9
bath
4
A-
Acetylstrophanthidin
Mg-Magnesium Fig.
2. Schematic
representation
of experimental
infusion sulphate
infusion
models.
hypomagnesemic digitalis toxicity, 2 to ‘7 C.C. of a 2.5 per cent magnesium sulfate solution was administered intravenously at a rate of approximately 1 c.c. per minute to several dogs in each group. Arterial blood samples, obtained during the control period prior to each infusion of acetyl strophanthidin and at the onset of digitalis toxicity, were analyzed for sodium and potassium by flame photometry and for magnesium and calcium by atomic absorption spectroscopy. Serum magnesium levels were also determined after the administration of magnesium sulfate. Blood pH was measured at intervals with a Radiometer pH meter. Results
Fucilitation of digitulis toxicity by hypomagneskzia. In both groups (I and II) the first infusion required 30 per cent more acetyl strophanthidin to produce a toxic arrhythmia than did the second infusion
because of an initial loading factor. In Group I, the dose required to produce digitalis toxicity during the second and third infusion did not vary significantly. This indicates that after the first infusion there was no statistically significant cumulative or carry-over effect from the second to the third infusion of acetyl strophanthidin in the presence of constant serum magnesium levels. (See statistical appendix A.) When serum magnesium levels were lowered by dialysis there was a statistically significant decrease in the amount of acetyl strophanthidin needed to produce an arrhythmia (p
Table I. Serum magnesium toxicity in Group I
and amount of acetyl strophanthidin
needed to produce digitalis 1
Groq I: Dog No.
~
C,*
1
AIt
/
Normal
Mg bath
Cz*
/
AZ?
Low
I
G*
1
(mEq./L.)i (fig/Kg.) , (mEq.lL.1; (Pg/‘Kg.) : bEn./L.) 11 13 14 15 16 19 20 21 Mean
1.54 1.35 1.35 1.50 1.56 1.70 1.74 1.40 1.52
64.3 44.5 69.3 35.9 33.8 55.0 50.2 51.5 50.5
1.57 1.56 1.36 1.64 1.80 1.85 2.04 1.50 1.67
*Cl. Ca, Ca. C4 = Serum Mg (mEq./L.) before first. second, tAl. AZ, Aa. A4 = Amount of acetyl strophantbidin (fig/Kg.) infusions.
Table II. Serum magnesium toxicity in Group II
41.8 33.0 36.2 26.9 30.0 38.5 34.3 36.8 34.7
Aat
Mg
C,*
/
(PdKg.)
(~&I./L.)\
42.8 35.7 36.2 35.9 43.8 35.7 41.7 40.4 39.0
1.27 0.92 0.85 1.25 1.23 1.19 1.12 0.85 1.09
1.61 1.58 1.53 1.75 1.85 1.93 1.87 1.49 1.70
third. and fourth infusions of acetyl strophanthidin. required to produce digitalis toxicity in the first.
and amount of acetyl strophanthidin
Normal
1
Mg
second,
bath
A:;(pglKg.1 33.7 26.1 38.1 38.1 20.0 21.1 17.8 29.4 28.0
third,
and fourth
needed to produce digitalis
bath
Group II: Dog No.
2 4 5 22 23 24 26 27 Mean
*Cl, Cz. Cat C4 = Serum tA1, AZ. Aa, A4 = Amount infusions.
2.15 2.01 1.50 1.59 1.03 1.02 1.61 2.08 1.62
72.1 70.6 49.2 84.6 47.9 59.1 34.5 57.7 59.5
Mg (mEq./L.) before of acetyl strophanthidin
2.22 1.73 1.67 1.66 1.15 1.00 1.69 2.34 1.68
first,
61.8 59.3 44.8 55.1 45.0 38.5 34.5 44.0 47.9
second. third, and fourth (*g/Kg.) required to produce
and 3 in Group III (Tables I, II, and III). Excluding data from the first infusion, the reduction (44 per cent) of serum magnesium levels from 1.67 to 0.93 mEq./L. resulted in a 26 per cent reduction in the toxic dose of acetyl strophanthidin from 42.4 to 31.4 ,ug per kilogram. Eficacy of magnesium sulfate in the treatment of digitalis toxicity associated with
;
1.63 0.94 1.13 0.85 0.68 0.53 0.94 1.09 0.97
infusions digitalis
33.5 57.9 32.0 50.0 43.2 30.2 21.9 27.5 37.0
of acetyl toxicity
0.79 0.99 0.84 0.45 0.44 0.90 0.86 0.75
stropbanthidin. in the first, second,
57.9 30.5 37.2 24.5 37.1 24.3 33.0 34.9
third,
and fourth
hypomagnesemia. Intravenous magnesium sulfate was administered to 17 dogs (8 in Group I, 6 in Group II, and 3 in Group III) in an attempt to correct the toxic arrhythmia associated with hypomagnesemia (Table IV). Restitution of sinus rhythm was observed in 13 dogs (76 per cent) almost immediately after intravenous administration of from 2 to 7 c.c. of a 25 per cent
Volume Number
79 1
Digitalis
Table III. Serum magnesium toxicity in Group III 1
c,*
toxicity and hypomagnesemia
and amount of acetyl strophanthidin
I
,
Low
i
bath
I
61
needed to produce digitalis
,
1
Nomzal~
bath
Group III: Dog No. (mEq./L.) 17 18 28 Mean
*CL Cz, Ca. G = Serum tA1. AS A:, & = Amount infusions.
1.11 1.45 1.33 1.30
(p$&.)
&:,L.)
45.9 46.7 60.2 50.9
0.94 1.12 0.81 0.96
Mg (mEq./LJ before of acetyl strophanthidin
first. second. (pg/Kg.)
(,g$&.) 34.4 44.4 26.6 35.1
(T&L.) 0.70 0.82 0.65 0.72
third, and fourth infusions required to produce digitalis
magnesium sulfate solution (Figs. 3 and 4). Magnesium sulfate failed to correct the arrhythmia in four dogs (Nos. 14, 15, 26, and 27). In two (Nos. 14 and 15) of this latter group, hypomagnesemia had not reduced the amount of digitalis necessary to induce digitalis toxicity (Table I). Duration of arrhythmia associated with hypomagnesemia as compared to those associated with normal magnesium levels. In Group II, the duration of the hypomagnesemia-facilitated arrhythmia following the third infusion of acetyl strophanthidin (DTI, Table IV) was not significantly longer than the arrhythmia induced after the second acetyl strophanthidin infusion (DT2, Table IV) in the presence of normal magnesium levels. In the 13 experiments in which magnesium sulfate abolished the arrhythmia, it is notable that reversion of the arrhythmia was effected within minutes and frequently within seconds of the drug administration. In these instances the duration of the arrhythmia was much shorter than when not treated with magnesium sulfate. Absence of cumulative e$ect of acetyl strophanthidin. In Group I, the dose of acetyl strophanthidin needed to produce digitalis toxicity was the same in the second as in the third infusion, demonstrating that under the conditions of this experiment, there was no cumulative or carryover effect of the acetyl strophanthidin. The experiment was reversed in Group III (Table III), so as to determine whether
(rg& 36.7 32.7 25.0 31.5
of acetyl toxicity
(T&L.)
(pz$&.)
1.53 1.47 1.72 1.57
strophanthidin. in the first, second,
37.9 36.2 35.9 36.7
third,
and fourth
the reduced dosage needed to produce digitalis toxicity during the fourth infusion of acetyl strophanthidin was due to accumulation of acetyl strophanthidin. Here, three dogs were initially dialyzed against a magnesium-free bath for six hours. Then 4 C.C. of a 25 per cent magnesium sulfate solution were infused and the dogs were dialyzed for an additional 3 hours with a normal magnesium bath. The amount of digitalis required during the fourth infusion of acetyl strophanthidin (with normal magnesium levels) was equal to or greater than the amounts required for the second and third (hypomagnesemic) infusions. This confirmed the fact that the reduction in the amount of acetyl strophanthidin needed to produce digitalis toxicity during all other experiments was due to hypomagnesemia rather than to the cumulative effect of acetyl strophanthidin. In Group III, prompt abolition of the arrhythmia associated with hypomagnesemia (third acetyl strophanthidin infusion) was accomplished by the administration of 4 cc. of 25 per cent magnesium sulfate, whereas magnesium salts were ineffective in correcting the digitalis toxicity associated with normomagnesemia (fourth acetyl strophanthidin infusion). Serum cation concentrations and PH. In 19 dogs (Groups I, II, and III), dialysis with a magnesium-free bath reduced serum magnesium levels from an average of 1.67 mEq./L. to 0.93 mEq./L., a decrease of 44 per cent. Potassium levels were un-
62
Seller
ct (II.
Table IV. ~ Mg Group I 11 13 14
13 11 13
1.61 1.58 1.53
13 18 1.5
1.27 0.92 0.85
2’ 3* lO*
2.4 6.87 8.06
1.5
14
13
1.75
7
1.25
10*
6.50
16 19 20 21
18 19 25 20
54 17 27 12
1.85 1.93 1.87 1.49
2 16 25 25
1.23 1.19 1.12 0.85
7* 6* 9* 7*
4.3 5.76 5.38 4.3
Group
Response
to 25 pev rent i!gS0~
and comment
*Sinus rhythm after 2 cc. MgSO( *Sinus rhythm after 6 C.C. MgSOa *9 CL. MgS04 without conversion to sinus rhythm; also no facilitation of digitalis toxicity by decreased magnesium *Temporary sinus rhythm after 4 C.C. MgSOd, then return of arrhythmia despite 14 C.C. MgSOa; also no facilitation of digitalis toxicity by decreased magnesium *Sinus rhythm after 5 C.C. MgSO, *Sinus rhythm after 6 cc. MgSO, *Sinus rhythm after 7 C.C. MgSOd *Sinus rhythm after 7 cc. MgSOd
II
2 4 5 22 23 24 26
15 27 16 7 12 8 16
2.22 1.73 1.67 1.66 1.15 1.00 1.69
14 14 18 7 22 19 22
1.63 0.94 1.13 0.85 0.68 0.53 0.94
ND 1.5 14 16 12 23 18
0.79 0.99 0.84 0.45 0.44 0.90
ND ND 5* 6* 3* 3* 20
27
8
2.34
12
1.09
10
0.86
14
Group III 17
10
0.94
10
0.7
2*
18
11
1.12
28
0.82
4*
28
16
0.81
10
0.65
5*
DT,. DT2, DT.q, and DTI = Duration (min.) CS, Ca. and CI = Serum Mg (mEq./L.) before Mg = Serum Mg after infusion of magnesium ND = Not determined.
9t
lot
of first, second. third. acetyl strophanthidin sulfate.
changed. No significant changes were noted in serum sodium or calcium levels during the experimental period. The pH remained constant. Electrocclrdiogruphic changes. A-V dissociation, nodal tachycardia, or ventricular tachycardia were taken as the end point of digitalis toxicity. For each individual animal, the arrhythmias induced during each infusion of acetyl strophanthidin were of the same type. Electrocardiographic
3t
3 78 5.71 1.97 4.89 8.27 8.57
3.43
4.63
3.26
and fourth infusion.
*Sinus rhythm after 6 C.C. MgS04 *Sinus rhythm after 6 C.C. MgSOd *Sinus rhythm after 2 C.C. MgSOa *Sinus rhythm after 4 C.C. MgSOa 13 C.C. MgSOa without conversion to sinus rhythm Temporary sinus rhythm after 6 C.C. MgSOd. then return of arrhythmia despite 10 C.C. MgS04
*Sinus
rhythm immediately after 2 cc. MgSO, tSinus rhythm after 6 cc. MgSOh *Sinus rhythm immediately after 4 C.C. MgSOa tArrhythmia persisted despite 4 C.C. MgS04 *Sinus rhythm after 4 C.C. MgSOh tSinus rhythm after 2 cc. MgSOd
arrhythmia.
changes associated with hypomagnesemia were primarily those of S-T-segment depression and T-wave inversion. Marked S-T-segment depression was seen in only a few experiments and did not correlate with the degree or duration of hypomagnesemia (Figs. 3 and 4). Discussion
Most studies relating electrolytes to the function and toxic manifestations of digi-
Digitalis
toxicity and hypomagnesemia
63
Fig. 3. After 3?5 hours of dialysis with a normal bath composition. A, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 1.67 mEq./L. B, Digitalis toxicity after infusion of 1,137 pg of acetyl strophanthidin (44.8 &g/Kg.). Serum magnesium 1.55 mEq./L. After three hours of dialysis with magnesiumfree bath. C, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 0.99 mEq./L. Note S-T-segment depression and T-wave inversion. D, Digitalis toxicity after infusion of 82.5 pg of acetyl strophanthidin (30.5 fig/Kg.). Serum magnesium 0.98 mEq./L. Hypomagnesemia facilitated the development of digitalis toxicity in that 27 per cent less acetyl strophanthidin was required than when the serum magnesium was 1.67 mEq./L. E, After 5 C.C. of a 25 per cent MgSOa solution given intravenously over a 5 minute period. Serum magnesium 3.78 mEq./L. Note the rapid abolition of digitalis toxicity and restitution of sinus rhythm subsequent to the correction of hypomagnesemia.
Fig. 4. After s hour of dialysis with a normal bath composition. A, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 1.56 mEq./L. I?, A-V dissociation after infusion of 67.5 pg ace&l strophanthidin (33.8 pg/Kg.). Serum magnesium 1.67 mEq./L. After three hours of dialysis with a magnesiumfree bath. C, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 1.23 mEq./L. Note S-T-segment depression and T-wave inversion. D, A-V dissociation after infusion of 400 rg acetyl strophanthidin (20.0 pg/Kg.). Serum magnesium 1.2 mEq./L. Hypomagnesemia facilitated the development of digitalis toxicity in that 40 per cent less acetyl strophanthidin was required than when the serum magnesium was 1.56 mEq./L. E, Sinus rhythm returned immediately after 2 C.C. of a 2.5 per cent MgS04 solution were administered intravenously over a two-minute period. Serum magnesium after a total of 5 C.C. of MgS04 = 4.3 mEq./L.
talk glycosides have dealt with potassium and calcium.“J2 They have shown that digitalis protects against the toxic manifestations of potassium and conversely that the administration of potassium salts protects the myocardium against digitalis toxicity.‘3 In addition, potassium depletion sensitizes
the myocardium to the development of digitalis toxicity.14 Other investigations have demonstrated that calcium affects myocardial contractibility and excitability and may occasionally potentiate the development of digitalis toxicity. Conversely, calcium chelating agents have been recom-
64
Seller
ct ctl.
17, High
.
diffu&tm
d, x+ ,
(K’)
Low UC3
Iii&
Low (??a’) 4
pnesive diffueion
of Na4
{r‘w
1
Fig. 5 A. Normal interrelationship of magnesium and digitalis with transmembrane electrolyte transport. The high intracellular concentration of K+ and the high extracellular concentration of Na+ results in passive diffusion of these ions away from these regions of high concentration. This is opposed by active transport of Na+ and K+ by the Na-K pump. This mechanism requires adenosine triphosphatase (ATPase) and its metalIocoenzyme Mg ++. Normally a high intracellular concentration of K+ is maintained as well as a low intracellular concentration of Na+.
INTRACELI
ULAR
SPACR
IN‘I’KRSTITIAL
SPACE
( K+)
w-a+) increases
Fig. 5 B. An interrelationship of magnesium and digitalis with transmembrane electrolyte transport in which digitalis blocks ATPase, resulting in a reduction of active transport of K+ into the cell while passive diffusion continues. This leads to a reduction in intracellular potassium. Hypomagnesemia also leads to a reduction in active transport of K+ into the cell resulting in a reduction in intracellular potassium.
C’olume Number
79 1
mended for the treatment of digitalis toxicity, but their therapeutic benefits are often evanescent.15J6 The primary cardiovascular effects of magnesium involve myocardial conduction and contraction as well as blood pressure regulation. Some investigators feel that magnesium depresses conduction and the spontaneous rhythm of the heart. They suggest that one of the mechanisms underlying these effects may be decreased loss of intracellular potassium as a result of reduction in membrane permeability to potassium.3 It is postulated that magnesium activates membrane adenosine triphosphatase, an enzyme responsible for active transport of cations across the cell membrane. Marked hypermagnesemia has dramatic cardiovascular effects which include vasodilatation, hypotension, and bradycardia; the effects of hypomagnesemia on the cardiovascular system are not clear.“-I9 Chronic magnesium deficiency in animals causes inflammatory, degenerative, and fibrotic changes in the myocardium, but no specific functional changes have been observed.20r21 The current study demonstrates that Kiil kidney dialysis is a hemodynamically stable method of inducing acute hypomagnesemia while maintaining other serum cation concentrations constant. Serum magnesium levels were reduced 44 per cent after 3 to 6 hours of dialysis with a magnesiumfree bath. The fact that this degree of hypomagnesemia reduces the toxic dose of acetyl strophanthidin by 26 per cent suggests that hypomagnesemia predisposes to the development of digitalis toxicity. Several studies have shown that chronic magnesium deficiency results in a reduction in intracellular potassium.3~4~22~23 This has been attributed to the fact that magnesium deficiency leads to disturbed oxidative phosphorylation which is essential for the maintenance of normal intracellular potassium concentrations. The decreased tolerance to acetyl strophanthidin observed in this study may be directly related to hypomagnesemia or possibly mediated by a decreased intracellular potassium concentration. In therapeutic doses, digitalis blocks adenosine triphosphatase activity in the cell membrane and thus inhibits active transmembrane transport of potassium.
Digitalis
toxicity and hy$omagnesemia
6.5
This results in a decrease in the intracellular potassium concentration (Fig. 5). Magnesium is a metallocoenzyme and activates adenosine triphosphatase. Hypomagnesemia may therefore contribute to digitalis adenosine triphosphatase blockade and result in a greater loss of intracellular potassium. These observations are of particular clinical significance in view of the fact that many diuretic drugs produce both hypokalemia and hypomagnesemia. The electrocardiographic changes associated with hypomagnesemia alone were S-T-segment depression and T-wave inversion. The S-T-segment depression was marked in some instances but did not correlate with the degree of hypomagnesemia. We did not observe peaking of the T wave in association with hypomagnesemia as described by other investigators.24 This may be due to rapid induction of hypomagnesemia by dialysis as compared to its slower production by feeding a magnesium-deficient diet. The fact that the electrocardiographic changes of hypomagnesemia (S-T-segment depression and Twave inversion) are similar to the changes of both hypokalemia and digitalis suggests that they have a common effect on myocardial repolarization. The effects of magnesium salts in various arrhythmias, including those induced by digitalis, have been studied by several investigators.gJO It has been shown that the slow intravenous infusion of 20 C.C. of a 20 per cent magnesium sulfate solution has little effect on the normal electrocardiogram and carries little clinical risk. Intravenous magnesium sulfate has been used to treat paroxysmal atria1 and ventricular tachycardia but atria1 fibrillation is not usually affected. It has been used with limited success in digitalis toxicity, but in these instances it was administered without determining serum magnesium levels. In this study, the intravenous infusion of 2 to 7 c.c. of a 2.5 per cent magnesium sulfate solution (1 C.C. per minute) abolished the toxic arrhythmia associated with hypomagnesemia in 13 of 17 animals (76 per cent). Its antiarrhythmic action was prompt and terminated the toxic arrhythmia permanently. As mentioned previously, magnesium sulfate was more effective in the treatment of digitalis toxicity
when the arrhythmia \\YIS associated with hypomagnesemia than when normal magnesium levels were present. Although the precise mechanism of its antiarrhythmic activity is not known, it may be due to correction of the hypomagnesemia. A second possibility supported by observations in our laboratory suggests that the administration of magnesium sulfate promotes the movement of potassium into the intracellular space. This would antagonize the effect of digitalis on intracellular potassium. A third possible explanation is that correction of the hypomagnesemia may decrease membrane permeability to calcium. This would result in a decreased intracellular movement of calcium which would also reduce the effect of digitalis. Summary
Four patients with digitalis toxicity were found to be hypomagnesemic and normokalemic. A significantly lower mean serum magnesium was noted in a group of digitalized heart failure patients (1.40 mEq./ L.) than in matched normal subjects (1.93 mEq./L.). These observations, coupled with the fact that both digitalis and magnesium deficiency lead to a decrease in intracellular potassium, suggested that hypomagnesemia might contribute to the development of digitalis toxicity. To determine whether hypomagnesemia facilitates the development of digitalis toxicity, serial acetyl strophanthidin infusions were performed in 19 adult mongrel dogs. Hypomagnesemia was achieved by Kiil kidney dialysis. While dialysate electrolyte concentration corresponded to normal canine plasma, acetyl strophanthidin was infused (100 pg per minute) three times at three hour intervals. Hypomagnesemia was then induced by three hours of magnesium-free dialysis and acetyl strophanthidin was again infused. Mean serum magnesium was reduced 44 per cent (1.67 to 0.93 mEq./L.). This was accompanied by a 26 per cent reduction in the amount of acetyl strophanthidin needed to produce a toxic arrhythmia (42.4 to 31.4 pg per kilogram). Restitution of sinus rhythm was observed in 13 dogs immediately after the intravenous infusion of 2 to 7 C.C.of 25 per cent magnesium sulfate.
These studies have shown that hypomagnesemia facilitates digitalis toxicity which can be promptly terminated with magnesium sulfate. Since diuretic drugs may produce hypomagnesemia as well as hypokalemia and both may predispose to digitalis toxicity, it is suggested that serum magnesium as well as potassium levels be determined in patients with digitalis toxicity. The authors greatly acknowledge the assistance rendered by Roberto Gomez.
technical
REFERENCES 1. Seller, R. II., Ramirez, O., Brest, A. N., and Moyer, J. H.: Serum and erythrocytic magnesium levels in congestive heart failure, Am. 1. Cardiol. 17:786. 1966. 2. j ac kson, C. E., and Meier, D. W.: Routine serum magnesium analysis, Ann. Int. Med. 69:743, 1968. 3. Skou, J. C.: Further investigation on a Mg++ and Na+ activated adenosine-triphosphatase, possibly related to the active, linked transport of Na+ and K+ across the nerve membrane, Biochem. & Bionhvs. Acta 42:6. 1960. 4. Post, R. L., Me&t, C. R., Kinsolving, C. R., and Albright, C. D.: Membrane adenosine triphosphatase as a participant in the active transport of sodium and potassium in the human erythrocyte, J. Biol. Chem. 235:1796, 1960. G., and Correa, 5. Vitale, J. J., Velez, H., Guzman, P.: Magnesium deficiency in the cebus monkey, Circulation Res. 12:642, 1963. 6. Vitale, J. J., Hellerstein, E. E., Nakamura, M., and Lown, B.: Effects of magnesium-deficient diet upon puppies, Circulation Res. 9:387, 1961. R. E., Katsutka, S., Vitale, J., and 7. Kleiger, Lown, B.: Effects of chronic depletion of potassium and magnesium upon the action of acetylstrophanthidin on the heart, Am. J. Cardiol. 17&20, 1966. 8. Kim. Y. W.. Andrews. C. E.. and Ruth. W. E.: Serum magnesium and cardiac arrhythmias with special reference to digitalis intoxication, Am. J. M. SC. 242:127, 1961. 9. Szekely, P., and Wynne, N. A.: Effects of magnesium on cardiac arrhythmias caused by digitalis, Clin. SC. 10:241, Ib.51. 10. Bellet. S.: Clinical disorders of the heart beat. ed. 1,‘Philadelphia. 19.53, Lea & Febiger, Pub: lishers, p, 215. B., Salzberg, H., Enselberg, C. D., and 11. Lown, Eston. R. E.: Interrelationship between potassium metabolism and digitalis-toxicity in- heart failure, Proc. Sot. Exper. Biol. & Med. 76:197, 1951. 12. Page, E., and Real, J. D.: Interrelationships between cardiac effects of ouabain, hypocalcemia and hyperkalemia, Circulation Res. 3:501, 195.5. J. J., Albertson, E. C., and Kondo, B.: 13. Sampson,
l~olume Number
14.
15.
16.
17.
18.
19.
79 1
Digitalis
The effect on man of potassium administration in relation to digitalis glycosides, AM. HEART J. 26:164, 1943. Lown, B., Weller, J. M., Wyatt, N., Hoigne, R., and Merrill, J. P.: Effects of alterations of body potassium on digitalis toxicity, J. Clin. Invest. 31:648, 1952. Jick, S., and Karsh, R.: The effect of calcium chelation on cardiac arrhythmias and conduction disturbances, Am. J. Cardiol. 4:287, 1959. Surawicz, B., MacDonald, M. G., Kaljot, V., and Bettinger, J. C.: Treatment of cardiac arrhythmias with salts of ethylenediamine tetraacetic acid (EDTA), AM. HEART J. 58:493, 19.59. Engbaek, L.: The pharmacologic action of magnesium ions with particular reference to the neuromuscular and cardiovascular systems, Pharmacol. Rev. 4:396, 1952. Bernstein, M. D.: Effect of intravenous magnesium on human heart, J. Lab. & Clin. Med. 25:131, 1939. Smith, P. K., Winkler, A. W., and Hoff, H. E.:
Appendix Table
22.
23.
24.
tables
Degrees of freedom
of variation
Between drugs Within drugs
Sums of squares
2 27 29
Total
5”
21.
Pharmacologic actions of parenterally administered salts, Anesthesiology 3:323, 1942. Moore, L. A., Hallman, E. T., and Sholl, L. B.: Cardiovascular and other lesions in calves fed diets low in magnesium, Arch. Path. 1:820, 1938. Greenberg, D. M., Anderson, C. E., and Tufts, E. V.: Pathological changes in the tissues of rats reared on diets low in magnesium, J. Biol. Chem. 114:43, 1936. Whang, R., and Welt, L. C.: Observations in experimental magnesium depletion, J. Clin. Invest. 42:305, 1963. Vitale, J. J., Nakamura, M., and Hegsted, D. M.: The effect of magnesium deficiency on oxidative phosphorylation, J. Biol. Chem. 228:573, 1957. Seta, K., Kleiger, R., Hellerstein, E. E., Lown, B., and Vitale, J. J.: Effect of potassium and magnesium deficiency on the electrocardiogram and plasma electrolytes of pure-bred beagles, Am. J. Cardiol. 17:516, 1966.
A. Sums of squares (toxicity)
Source
Table
20.
Mean square
!
1010.6487 27’18.7580
505.3244 100.6947
3729.4067
B.
1.67 1.73
44.8 59.3
1.13 0.94
57.9 32.0
0.79 0.99
30.5 57.9
22 23 24
1.66 1.15 1.00
55.1 45.0 38.5
0.85 0.68 0.53
50.0 43.2 30.2
0.84 0.45 0.44
37.2 24.5 37.1
26 27 17 18 28
1.69 2.34 1.11 1.45 1.33
34.5 44.0 45.9 46.7 60.2 __ 474.0 47.4
0.94 1.09 0.94 1.12 0.81
21.9 27.5 34.4 44.4 26.6
0.90 0.86 0.70 0.82 0.65
24.3 33.0 36.7 32.7 25.0
9.03 0.903
368.1 36.81
7.44 0.744
338.9 33.89
Total Means
67
toxicity and hypomagnesemia
15.13 1.513
--
_
31.6 -
31.6 1.053
1181 1181 393.67
68
Seller et 01.
Table C. Analysis
of covarinnce:
F-test; one-way cltrssijkation I
Deviation
; D.O.F.
regression
~ i
i sum of sq.
i
from
D.O. F.
ZC”
1
XA
~
ZAZ
Reduction
I Treatments Error
2 27 29
TSE
Statistical
A.
3.2958 2.0469 ___ 5.3427
57.7112 4.2221
1010.6487 2718.7580
61.9333
3729.4067
appendix*
To test whether there was a cumulative or carry-over effect from the acetyl strophanthidin infusions in the presence of constant magnesium, the data As-A, from Table I was used in a Wilcoxon Signed Rank test.
ArAz Ranks
2,
, 6
-8,
Aa-AS -1,
-11,
3, -5,
-2,
104.233
3011.4675 301.4183
150.709
tally significant at the 0.05 level. The hypothesis of no drop in acetyl strophanthidin tolerance has been rejected. C. To determine if the difference in means if the toxic amount of acetyl strophanthidin is directly related to the decrease in serum magnesium the
7,
-3,
5,
4
-8.3,-12.6,-1615
The appropriate statistic is T which is the absolute value of the sum of the negative ranks. The 0.05 cut-off point is 2, so that this value of T = 3 is not statistically significant at the 0.05 level. Hence the hypothesis of no cumulative effect has not been rejected at the 0.05 level. B. To test whether there was a drop in acetyl strophanthidin tolerance in the presence of hypomagnesemia, the data Ad-A8 from Table I was pooled with As-AZ from Table II. The Wilcoxon Signed Rank test was used again. The appropriate ranks are as follows: -7,
2710.0492
-9.6,+1.9,+2.2,-23.8,-14.6,-23.9,--11.0
A3-AZ-1.4,-12.8,-S.l,--1.8,
Ad-A3
26 28 2
+1.0,+2.7,0,+9.0,+13.8,-2.8,+7.4,+3.6 1,
AI-A,-9.1,
8.7088 ____ 717.9392
Mean square
4, -14,
-12,
-155,
-6,
-10,
-13
-9
In this instance, T = 7. The 0.05 cutoff point is 2.5, so that this is statisti*The foIlowing references were consulted: Wilcoxon. F., and Wilcox, R. A.: Some rapid approximate statistical procedures, Pearl River. N. Y., 1964, Lederie Laboratories Monograph. Snedecor. G. W., and Cochran, W. G.: Statistical methods, ed. 6, Ames. Iowa. 1967. Iowa State University Press.
question arises as to what effect the elimination of the magnesium removal as a concomitant variable will have on the difference in means in acetyl strophanthidin tolerance. We used the values of AZ, A,, and A4 in Table II pooled with the values of Ai, A?, and Aa in Table III (Table A). Fa, 27 = 5.0184 > 3.35 (significant at the 5 per cent level). This F value is significant. Next, an analysis of covariance was performed to eliminate the effect of the magnesium removal. The data are listed in Table B. Ff, 26 = 150.7092/104.233 = 1.446. This is not significant. The estimated slope of the regression is (4.221)/2.0469 = 2.0627. The adjusted means for the toxicity tolerance becomes for I: 47.4 II: 36.81 III: 33.89 -
2.0627 2.0627 2.0627
(1.513 (0.903 (0.744
-
1.053) 1.053) 1.053)
= 46.45 = 37.12 = 34.53.
Since these adjusted means are not significant, the removal of the magnesium effect has removed the differences in acetyl strophanthidin tolerance.
and laboratory
Digitalis
toxicity
reports
and
hypomagnesemia
Robert H. Seller, M.D. Jose Cangiano, M.D. Kwan E. Kim, M.D. Saul Mendelssohn, M.D. Albert N. Brest, M.D. Charles Swartz, M.D. Philadelphia, Pa.
I
n a prior study,’ we observed that serum magnesium levels were significantly lower in 13 digitalized patients with congestive heart failure (1.40 mEq. per liter [mEq./L.]) than in 72 control subjects (1.93 mEq./L.) Jackson and Meier2 noted an excessive prevalence of hypomagnesemia in patients on diuretic drugs. We found frank hypomagnesemia in four patients with digitalis toxicity. These observations, coupled with the fact that magnesium deficiency leads to an intracellular deficit of potassium,3*4 suggested that hypomagnesemia contributes to the development of digitalis toxicity. While some investigators have shown that the induction of hypomagnesemia (by feeding growing puppies a diet deficient in magnesium) facilitates the development of digitalis toxicity,5*6 others were unable to confirm this finding. Kleiger and associates7 observed that the arrhythmia produced by acetylstrophanthidin persisted longer in From the Section of Nephrology and Vascular This study was supported by funds from the No. HE 08052). and the Heart Association The statistical and computational portion of Center which is supported by the Special 00266). Received for publication Jan. 20, 1969. Reprint requests to: Dr. Seller, Department St., Philadelphia, Pa.
Vol.
79, No.
1, pp. 57-68
January,
1970
hypomagnesemic than in normal dogs. Kim and co-workers8 observed a small but significant rise in serum magnesium concentration in patients subsequent to the dissipation of digitoxic arrhythmias. In most studies utilizing parenteral magnesium salts in the treatment of digitalis toxicity, they were given empirically without determining plasma magnesium concentrations.97’0 The resultant transient antiarrhythmic activity of magnesium salts may be analogous to the administration of potassium to normokalemic patients with digitalis toxicity. In these instances, potassium salts often have limited usefulness and may further depress atrioventricular conduction. In contrast, potassium salts are particularly effective when digitalis toxicity is associated with hypokalemia. The purpose of this investigation was twofold: (1) to determine whether hypomagnesemia facilitates the development of digitalis toxicity; and (2) to determine the
Diseases, Hahnemann Medical College and Hospital, Philadelphia, Pa. United States Public Health Service, the National Heart Institute (Grant of Southeastern Pennsylvania. this study was performed at the Hahnemann Medical College Computer Resources Branch of the National Institutes of Health (Grant No. FR-
of Medicine,
Hahnemann
Medical
College
American
and
Hospital,
230 N. Broad
Heart Journal
57
5r ! *Beam
Bolonce
Intro-orteriol blood pressure monitoring
Infusion pump v-Acetylstrophonthidin
Mg’t + Free Diolyrote Fig.
1. Schematic
drawing
of animal
experiment
efficacy of intravenously administered magnesium sulfate in the treatment of digitalis toxicity associated with hypomagnesemia. Methods
and
materials
Studies were performed in 19 adult mongrel dogs whose average weight was 20 kilograms. Anesthesia was induced by 25 mg. per kilogram of intravenous Pentothal Sodium and additional doses were given as needed to maintain anesthesia. The dogs were ventilated through a cuffed endotracheal tube with a Harvard respirator whose tidal volume and rate were adjusted to dog weight. The dogs were hydrated with 300 C.C. of isotonic saline. A two-layer Kiil kidney hemodialysis, primed with 300 C.C. of normal saline, was started using femoral arterial and venous cannulations. Magnesium-free deionized water was used for the dialysate bath. The following substances were added to 100 liters of deionized water: NaCl, 620 Gm. ; NaHC03, 300 Gm.; KCl, 30 Gm.; MgC12, 12 Gm.; CaC12, 22 Gm.; lactic acid, 40 c.c.; and glucose, 100 Gm. This resulted in cation concentrations which approximated the
ionized iraction found in normal r;LliiIic. plasma: Sa, 141 mEq./L.; K, 4.0 mEq./L.; Mg, 1.3 mEq.,/‘L.; Ca, 3.0 mEq.jL.; (Jl, 116 mEq./L.; and HCOI, 35 mEq./L. During dialysis the dog’s weight was continuously monitored on a beam balance, and isotonic saline replacement I\-as given in order to maintain a constant weight. Continuous intraarterial blood pressure was determined with a strain-gauge transducer and monitored on an oscilloscope. Serial Lead II electrocardiograms were obtained with a direct-writing electrocardiograph (Fig. 1). Acetyl strophanthidin \vas infused through an indwelling venous catheter at a rate of 100 pg per minute by means of a constant infusion pump. The infusion was continued until the onset of digitalis toxicity, as evidenced by A-V dissociation, nodal tachycardia, or ventricular tachycardia. All dogs were dialyzed with a normal bath as well as a bath identical in composition but free of magnesium. Three groups of animals were studied (Fig. 2). Groz~p I. Eight dogs had infusions of acetyl strophanthidin after fs, 3j5, and 656 hours of dialysis with a normal bath. The fourth acetyl strophanthidin infusion was performed after 3 additional hours of dialysis utilizing the magnesium-free dialysate. Group II. Eight dogs had infusions of acetyl strophanthidin after ?,s and 355 hours of dialysis with a normal bath. The third and fourth acetyl strophanthidin infusions were performed after 3 and 6 additional hours of dialysis with the magnesium-free dialysate. Group III. In order to assure that there was no cumulative effect due to repeated digitalization, the experiment was reversed. Three dogs had acetyl strophanthidin infusions performed at M, 35$, and 655 hours of dialysis with a magnesiumfree bath. Then 4 C.C. of a 25 per cent magnesium sulfate solution was injected intravenously to correct the hypomagnesemia and terminate the arrhythmia. The fourth acetyl strophanthidin infusion was performed after 3 additional hours of dialysis with a normal bath. In order to determine the efficacy of magnesium sulfate in the treatment of
VollLmc Nlcmber
79
Digitalis
1
toxicity and hypomagnesemia
59
GROUP I (8 DOGS)
GROUP II (8 DOGS)
GROUP III (3 DOGS)
0 ‘+
I
2
3
Dialysis
4
with
5 HOURS
magnesium
6
7
free
8
9
bath
4
A-
Acetylstrophanthidin
Mg-Magnesium Fig.
2. Schematic
representation
of experimental
infusion sulphate
infusion
models.
hypomagnesemic digitalis toxicity, 2 to ‘7 C.C. of a 2.5 per cent magnesium sulfate solution was administered intravenously at a rate of approximately 1 c.c. per minute to several dogs in each group. Arterial blood samples, obtained during the control period prior to each infusion of acetyl strophanthidin and at the onset of digitalis toxicity, were analyzed for sodium and potassium by flame photometry and for magnesium and calcium by atomic absorption spectroscopy. Serum magnesium levels were also determined after the administration of magnesium sulfate. Blood pH was measured at intervals with a Radiometer pH meter. Results
Fucilitation of digitulis toxicity by hypomagneskzia. In both groups (I and II) the first infusion required 30 per cent more acetyl strophanthidin to produce a toxic arrhythmia than did the second infusion
because of an initial loading factor. In Group I, the dose required to produce digitalis toxicity during the second and third infusion did not vary significantly. This indicates that after the first infusion there was no statistically significant cumulative or carry-over effect from the second to the third infusion of acetyl strophanthidin in the presence of constant serum magnesium levels. (See statistical appendix A.) When serum magnesium levels were lowered by dialysis there was a statistically significant decrease in the amount of acetyl strophanthidin needed to produce an arrhythmia (p
Table I. Serum magnesium toxicity in Group I
and amount of acetyl strophanthidin
needed to produce digitalis 1
Groq I: Dog No.
~
C,*
1
AIt
/
Normal
Mg bath
Cz*
/
AZ?
Low
I
G*
1
(mEq./L.)i (fig/Kg.) , (mEq.lL.1; (Pg/‘Kg.) : bEn./L.) 11 13 14 15 16 19 20 21 Mean
1.54 1.35 1.35 1.50 1.56 1.70 1.74 1.40 1.52
64.3 44.5 69.3 35.9 33.8 55.0 50.2 51.5 50.5
1.57 1.56 1.36 1.64 1.80 1.85 2.04 1.50 1.67
*Cl. Ca, Ca. C4 = Serum Mg (mEq./L.) before first. second, tAl. AZ, Aa. A4 = Amount of acetyl strophantbidin (fig/Kg.) infusions.
Table II. Serum magnesium toxicity in Group II
41.8 33.0 36.2 26.9 30.0 38.5 34.3 36.8 34.7
Aat
Mg
C,*
/
(PdKg.)
(~&I./L.)\
42.8 35.7 36.2 35.9 43.8 35.7 41.7 40.4 39.0
1.27 0.92 0.85 1.25 1.23 1.19 1.12 0.85 1.09
1.61 1.58 1.53 1.75 1.85 1.93 1.87 1.49 1.70
third. and fourth infusions of acetyl strophanthidin. required to produce digitalis toxicity in the first.
and amount of acetyl strophanthidin
Normal
1
Mg
second,
bath
A:;(pglKg.1 33.7 26.1 38.1 38.1 20.0 21.1 17.8 29.4 28.0
third,
and fourth
needed to produce digitalis
bath
Group II: Dog No.
2 4 5 22 23 24 26 27 Mean
*Cl, Cz. Cat C4 = Serum tA1, AZ. Aa, A4 = Amount infusions.
2.15 2.01 1.50 1.59 1.03 1.02 1.61 2.08 1.62
72.1 70.6 49.2 84.6 47.9 59.1 34.5 57.7 59.5
Mg (mEq./L.) before of acetyl strophanthidin
2.22 1.73 1.67 1.66 1.15 1.00 1.69 2.34 1.68
first,
61.8 59.3 44.8 55.1 45.0 38.5 34.5 44.0 47.9
second. third, and fourth (*g/Kg.) required to produce
and 3 in Group III (Tables I, II, and III). Excluding data from the first infusion, the reduction (44 per cent) of serum magnesium levels from 1.67 to 0.93 mEq./L. resulted in a 26 per cent reduction in the toxic dose of acetyl strophanthidin from 42.4 to 31.4 ,ug per kilogram. Eficacy of magnesium sulfate in the treatment of digitalis toxicity associated with
;
1.63 0.94 1.13 0.85 0.68 0.53 0.94 1.09 0.97
infusions digitalis
33.5 57.9 32.0 50.0 43.2 30.2 21.9 27.5 37.0
of acetyl toxicity
0.79 0.99 0.84 0.45 0.44 0.90 0.86 0.75
stropbanthidin. in the first, second,
57.9 30.5 37.2 24.5 37.1 24.3 33.0 34.9
third,
and fourth
hypomagnesemia. Intravenous magnesium sulfate was administered to 17 dogs (8 in Group I, 6 in Group II, and 3 in Group III) in an attempt to correct the toxic arrhythmia associated with hypomagnesemia (Table IV). Restitution of sinus rhythm was observed in 13 dogs (76 per cent) almost immediately after intravenous administration of from 2 to 7 c.c. of a 25 per cent
Volume Number
79 1
Digitalis
Table III. Serum magnesium toxicity in Group III 1
c,*
toxicity and hypomagnesemia
and amount of acetyl strophanthidin
I
,
Low
i
bath
I
61
needed to produce digitalis
,
1
Nomzal~
bath
Group III: Dog No. (mEq./L.) 17 18 28 Mean
*CL Cz, Ca. G = Serum tA1. AS A:, & = Amount infusions.
1.11 1.45 1.33 1.30
(p$&.)
&:,L.)
45.9 46.7 60.2 50.9
0.94 1.12 0.81 0.96
Mg (mEq./LJ before of acetyl strophanthidin
first. second. (pg/Kg.)
(,g$&.) 34.4 44.4 26.6 35.1
(T&L.) 0.70 0.82 0.65 0.72
third, and fourth infusions required to produce digitalis
magnesium sulfate solution (Figs. 3 and 4). Magnesium sulfate failed to correct the arrhythmia in four dogs (Nos. 14, 15, 26, and 27). In two (Nos. 14 and 15) of this latter group, hypomagnesemia had not reduced the amount of digitalis necessary to induce digitalis toxicity (Table I). Duration of arrhythmia associated with hypomagnesemia as compared to those associated with normal magnesium levels. In Group II, the duration of the hypomagnesemia-facilitated arrhythmia following the third infusion of acetyl strophanthidin (DTI, Table IV) was not significantly longer than the arrhythmia induced after the second acetyl strophanthidin infusion (DT2, Table IV) in the presence of normal magnesium levels. In the 13 experiments in which magnesium sulfate abolished the arrhythmia, it is notable that reversion of the arrhythmia was effected within minutes and frequently within seconds of the drug administration. In these instances the duration of the arrhythmia was much shorter than when not treated with magnesium sulfate. Absence of cumulative e$ect of acetyl strophanthidin. In Group I, the dose of acetyl strophanthidin needed to produce digitalis toxicity was the same in the second as in the third infusion, demonstrating that under the conditions of this experiment, there was no cumulative or carryover effect of the acetyl strophanthidin. The experiment was reversed in Group III (Table III), so as to determine whether
(rg& 36.7 32.7 25.0 31.5
of acetyl toxicity
(T&L.)
(pz$&.)
1.53 1.47 1.72 1.57
strophanthidin. in the first, second,
37.9 36.2 35.9 36.7
third,
and fourth
the reduced dosage needed to produce digitalis toxicity during the fourth infusion of acetyl strophanthidin was due to accumulation of acetyl strophanthidin. Here, three dogs were initially dialyzed against a magnesium-free bath for six hours. Then 4 C.C. of a 25 per cent magnesium sulfate solution were infused and the dogs were dialyzed for an additional 3 hours with a normal magnesium bath. The amount of digitalis required during the fourth infusion of acetyl strophanthidin (with normal magnesium levels) was equal to or greater than the amounts required for the second and third (hypomagnesemic) infusions. This confirmed the fact that the reduction in the amount of acetyl strophanthidin needed to produce digitalis toxicity during all other experiments was due to hypomagnesemia rather than to the cumulative effect of acetyl strophanthidin. In Group III, prompt abolition of the arrhythmia associated with hypomagnesemia (third acetyl strophanthidin infusion) was accomplished by the administration of 4 cc. of 25 per cent magnesium sulfate, whereas magnesium salts were ineffective in correcting the digitalis toxicity associated with normomagnesemia (fourth acetyl strophanthidin infusion). Serum cation concentrations and PH. In 19 dogs (Groups I, II, and III), dialysis with a magnesium-free bath reduced serum magnesium levels from an average of 1.67 mEq./L. to 0.93 mEq./L., a decrease of 44 per cent. Potassium levels were un-
62
Seller
ct (II.
Table IV. ~ Mg Group I 11 13 14
13 11 13
1.61 1.58 1.53
13 18 1.5
1.27 0.92 0.85
2’ 3* lO*
2.4 6.87 8.06
1.5
14
13
1.75
7
1.25
10*
6.50
16 19 20 21
18 19 25 20
54 17 27 12
1.85 1.93 1.87 1.49
2 16 25 25
1.23 1.19 1.12 0.85
7* 6* 9* 7*
4.3 5.76 5.38 4.3
Group
Response
to 25 pev rent i!gS0~
and comment
*Sinus rhythm after 2 cc. MgSO( *Sinus rhythm after 6 C.C. MgSOa *9 CL. MgS04 without conversion to sinus rhythm; also no facilitation of digitalis toxicity by decreased magnesium *Temporary sinus rhythm after 4 C.C. MgSOd, then return of arrhythmia despite 14 C.C. MgSOa; also no facilitation of digitalis toxicity by decreased magnesium *Sinus rhythm after 5 C.C. MgSO, *Sinus rhythm after 6 cc. MgSO, *Sinus rhythm after 7 C.C. MgSOd *Sinus rhythm after 7 cc. MgSOd
II
2 4 5 22 23 24 26
15 27 16 7 12 8 16
2.22 1.73 1.67 1.66 1.15 1.00 1.69
14 14 18 7 22 19 22
1.63 0.94 1.13 0.85 0.68 0.53 0.94
ND 1.5 14 16 12 23 18
0.79 0.99 0.84 0.45 0.44 0.90
ND ND 5* 6* 3* 3* 20
27
8
2.34
12
1.09
10
0.86
14
Group III 17
10
0.94
10
0.7
2*
18
11
1.12
28
0.82
4*
28
16
0.81
10
0.65
5*
DT,. DT2, DT.q, and DTI = Duration (min.) CS, Ca. and CI = Serum Mg (mEq./L.) before Mg = Serum Mg after infusion of magnesium ND = Not determined.
9t
lot
of first, second. third. acetyl strophanthidin sulfate.
changed. No significant changes were noted in serum sodium or calcium levels during the experimental period. The pH remained constant. Electrocclrdiogruphic changes. A-V dissociation, nodal tachycardia, or ventricular tachycardia were taken as the end point of digitalis toxicity. For each individual animal, the arrhythmias induced during each infusion of acetyl strophanthidin were of the same type. Electrocardiographic
3t
3 78 5.71 1.97 4.89 8.27 8.57
3.43
4.63
3.26
and fourth infusion.
*Sinus rhythm after 6 C.C. MgS04 *Sinus rhythm after 6 C.C. MgSOd *Sinus rhythm after 2 C.C. MgSOa *Sinus rhythm after 4 C.C. MgSOa 13 C.C. MgSOa without conversion to sinus rhythm Temporary sinus rhythm after 6 C.C. MgSOd. then return of arrhythmia despite 10 C.C. MgS04
*Sinus
rhythm immediately after 2 cc. MgSO, tSinus rhythm after 6 cc. MgSOh *Sinus rhythm immediately after 4 C.C. MgSOa tArrhythmia persisted despite 4 C.C. MgS04 *Sinus rhythm after 4 C.C. MgSOh tSinus rhythm after 2 cc. MgSOd
arrhythmia.
changes associated with hypomagnesemia were primarily those of S-T-segment depression and T-wave inversion. Marked S-T-segment depression was seen in only a few experiments and did not correlate with the degree or duration of hypomagnesemia (Figs. 3 and 4). Discussion
Most studies relating electrolytes to the function and toxic manifestations of digi-
Digitalis
toxicity and hypomagnesemia
63
Fig. 3. After 3?5 hours of dialysis with a normal bath composition. A, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 1.67 mEq./L. B, Digitalis toxicity after infusion of 1,137 pg of acetyl strophanthidin (44.8 &g/Kg.). Serum magnesium 1.55 mEq./L. After three hours of dialysis with magnesiumfree bath. C, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 0.99 mEq./L. Note S-T-segment depression and T-wave inversion. D, Digitalis toxicity after infusion of 82.5 pg of acetyl strophanthidin (30.5 fig/Kg.). Serum magnesium 0.98 mEq./L. Hypomagnesemia facilitated the development of digitalis toxicity in that 27 per cent less acetyl strophanthidin was required than when the serum magnesium was 1.67 mEq./L. E, After 5 C.C. of a 25 per cent MgSOa solution given intravenously over a 5 minute period. Serum magnesium 3.78 mEq./L. Note the rapid abolition of digitalis toxicity and restitution of sinus rhythm subsequent to the correction of hypomagnesemia.
Fig. 4. After s hour of dialysis with a normal bath composition. A, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 1.56 mEq./L. I?, A-V dissociation after infusion of 67.5 pg ace&l strophanthidin (33.8 pg/Kg.). Serum magnesium 1.67 mEq./L. After three hours of dialysis with a magnesiumfree bath. C, Sinus rhythm before acetyl strophanthidin infusion. Serum magnesium 1.23 mEq./L. Note S-T-segment depression and T-wave inversion. D, A-V dissociation after infusion of 400 rg acetyl strophanthidin (20.0 pg/Kg.). Serum magnesium 1.2 mEq./L. Hypomagnesemia facilitated the development of digitalis toxicity in that 40 per cent less acetyl strophanthidin was required than when the serum magnesium was 1.56 mEq./L. E, Sinus rhythm returned immediately after 2 C.C. of a 2.5 per cent MgS04 solution were administered intravenously over a two-minute period. Serum magnesium after a total of 5 C.C. of MgS04 = 4.3 mEq./L.
talk glycosides have dealt with potassium and calcium.“J2 They have shown that digitalis protects against the toxic manifestations of potassium and conversely that the administration of potassium salts protects the myocardium against digitalis toxicity.‘3 In addition, potassium depletion sensitizes
the myocardium to the development of digitalis toxicity.14 Other investigations have demonstrated that calcium affects myocardial contractibility and excitability and may occasionally potentiate the development of digitalis toxicity. Conversely, calcium chelating agents have been recom-
64
Seller
ct ctl.
17, High
.
diffu&tm
d, x+ ,
(K’)
Low UC3
Iii&
Low (??a’) 4
pnesive diffueion
of Na4
{r‘w
1
Fig. 5 A. Normal interrelationship of magnesium and digitalis with transmembrane electrolyte transport. The high intracellular concentration of K+ and the high extracellular concentration of Na+ results in passive diffusion of these ions away from these regions of high concentration. This is opposed by active transport of Na+ and K+ by the Na-K pump. This mechanism requires adenosine triphosphatase (ATPase) and its metalIocoenzyme Mg ++. Normally a high intracellular concentration of K+ is maintained as well as a low intracellular concentration of Na+.
INTRACELI
ULAR
SPACR
IN‘I’KRSTITIAL
SPACE
( K+)
w-a+) increases
Fig. 5 B. An interrelationship of magnesium and digitalis with transmembrane electrolyte transport in which digitalis blocks ATPase, resulting in a reduction of active transport of K+ into the cell while passive diffusion continues. This leads to a reduction in intracellular potassium. Hypomagnesemia also leads to a reduction in active transport of K+ into the cell resulting in a reduction in intracellular potassium.
C’olume Number
79 1
mended for the treatment of digitalis toxicity, but their therapeutic benefits are often evanescent.15J6 The primary cardiovascular effects of magnesium involve myocardial conduction and contraction as well as blood pressure regulation. Some investigators feel that magnesium depresses conduction and the spontaneous rhythm of the heart. They suggest that one of the mechanisms underlying these effects may be decreased loss of intracellular potassium as a result of reduction in membrane permeability to potassium.3 It is postulated that magnesium activates membrane adenosine triphosphatase, an enzyme responsible for active transport of cations across the cell membrane. Marked hypermagnesemia has dramatic cardiovascular effects which include vasodilatation, hypotension, and bradycardia; the effects of hypomagnesemia on the cardiovascular system are not clear.“-I9 Chronic magnesium deficiency in animals causes inflammatory, degenerative, and fibrotic changes in the myocardium, but no specific functional changes have been observed.20r21 The current study demonstrates that Kiil kidney dialysis is a hemodynamically stable method of inducing acute hypomagnesemia while maintaining other serum cation concentrations constant. Serum magnesium levels were reduced 44 per cent after 3 to 6 hours of dialysis with a magnesiumfree bath. The fact that this degree of hypomagnesemia reduces the toxic dose of acetyl strophanthidin by 26 per cent suggests that hypomagnesemia predisposes to the development of digitalis toxicity. Several studies have shown that chronic magnesium deficiency results in a reduction in intracellular potassium.3~4~22~23 This has been attributed to the fact that magnesium deficiency leads to disturbed oxidative phosphorylation which is essential for the maintenance of normal intracellular potassium concentrations. The decreased tolerance to acetyl strophanthidin observed in this study may be directly related to hypomagnesemia or possibly mediated by a decreased intracellular potassium concentration. In therapeutic doses, digitalis blocks adenosine triphosphatase activity in the cell membrane and thus inhibits active transmembrane transport of potassium.
Digitalis
toxicity and hy$omagnesemia
6.5
This results in a decrease in the intracellular potassium concentration (Fig. 5). Magnesium is a metallocoenzyme and activates adenosine triphosphatase. Hypomagnesemia may therefore contribute to digitalis adenosine triphosphatase blockade and result in a greater loss of intracellular potassium. These observations are of particular clinical significance in view of the fact that many diuretic drugs produce both hypokalemia and hypomagnesemia. The electrocardiographic changes associated with hypomagnesemia alone were S-T-segment depression and T-wave inversion. The S-T-segment depression was marked in some instances but did not correlate with the degree of hypomagnesemia. We did not observe peaking of the T wave in association with hypomagnesemia as described by other investigators.24 This may be due to rapid induction of hypomagnesemia by dialysis as compared to its slower production by feeding a magnesium-deficient diet. The fact that the electrocardiographic changes of hypomagnesemia (S-T-segment depression and Twave inversion) are similar to the changes of both hypokalemia and digitalis suggests that they have a common effect on myocardial repolarization. The effects of magnesium salts in various arrhythmias, including those induced by digitalis, have been studied by several investigators.gJO It has been shown that the slow intravenous infusion of 20 C.C. of a 20 per cent magnesium sulfate solution has little effect on the normal electrocardiogram and carries little clinical risk. Intravenous magnesium sulfate has been used to treat paroxysmal atria1 and ventricular tachycardia but atria1 fibrillation is not usually affected. It has been used with limited success in digitalis toxicity, but in these instances it was administered without determining serum magnesium levels. In this study, the intravenous infusion of 2 to 7 c.c. of a 2.5 per cent magnesium sulfate solution (1 C.C. per minute) abolished the toxic arrhythmia associated with hypomagnesemia in 13 of 17 animals (76 per cent). Its antiarrhythmic action was prompt and terminated the toxic arrhythmia permanently. As mentioned previously, magnesium sulfate was more effective in the treatment of digitalis toxicity
when the arrhythmia \\YIS associated with hypomagnesemia than when normal magnesium levels were present. Although the precise mechanism of its antiarrhythmic activity is not known, it may be due to correction of the hypomagnesemia. A second possibility supported by observations in our laboratory suggests that the administration of magnesium sulfate promotes the movement of potassium into the intracellular space. This would antagonize the effect of digitalis on intracellular potassium. A third possible explanation is that correction of the hypomagnesemia may decrease membrane permeability to calcium. This would result in a decreased intracellular movement of calcium which would also reduce the effect of digitalis. Summary
Four patients with digitalis toxicity were found to be hypomagnesemic and normokalemic. A significantly lower mean serum magnesium was noted in a group of digitalized heart failure patients (1.40 mEq./ L.) than in matched normal subjects (1.93 mEq./L.). These observations, coupled with the fact that both digitalis and magnesium deficiency lead to a decrease in intracellular potassium, suggested that hypomagnesemia might contribute to the development of digitalis toxicity. To determine whether hypomagnesemia facilitates the development of digitalis toxicity, serial acetyl strophanthidin infusions were performed in 19 adult mongrel dogs. Hypomagnesemia was achieved by Kiil kidney dialysis. While dialysate electrolyte concentration corresponded to normal canine plasma, acetyl strophanthidin was infused (100 pg per minute) three times at three hour intervals. Hypomagnesemia was then induced by three hours of magnesium-free dialysis and acetyl strophanthidin was again infused. Mean serum magnesium was reduced 44 per cent (1.67 to 0.93 mEq./L.). This was accompanied by a 26 per cent reduction in the amount of acetyl strophanthidin needed to produce a toxic arrhythmia (42.4 to 31.4 pg per kilogram). Restitution of sinus rhythm was observed in 13 dogs immediately after the intravenous infusion of 2 to 7 C.C.of 25 per cent magnesium sulfate.
These studies have shown that hypomagnesemia facilitates digitalis toxicity which can be promptly terminated with magnesium sulfate. Since diuretic drugs may produce hypomagnesemia as well as hypokalemia and both may predispose to digitalis toxicity, it is suggested that serum magnesium as well as potassium levels be determined in patients with digitalis toxicity. The authors greatly acknowledge the assistance rendered by Roberto Gomez.
technical
REFERENCES 1. Seller, R. II., Ramirez, O., Brest, A. N., and Moyer, J. H.: Serum and erythrocytic magnesium levels in congestive heart failure, Am. 1. Cardiol. 17:786. 1966. 2. j ac kson, C. E., and Meier, D. W.: Routine serum magnesium analysis, Ann. Int. Med. 69:743, 1968. 3. Skou, J. C.: Further investigation on a Mg++ and Na+ activated adenosine-triphosphatase, possibly related to the active, linked transport of Na+ and K+ across the nerve membrane, Biochem. & Bionhvs. Acta 42:6. 1960. 4. Post, R. L., Me&t, C. R., Kinsolving, C. R., and Albright, C. D.: Membrane adenosine triphosphatase as a participant in the active transport of sodium and potassium in the human erythrocyte, J. Biol. Chem. 235:1796, 1960. G., and Correa, 5. Vitale, J. J., Velez, H., Guzman, P.: Magnesium deficiency in the cebus monkey, Circulation Res. 12:642, 1963. 6. Vitale, J. J., Hellerstein, E. E., Nakamura, M., and Lown, B.: Effects of magnesium-deficient diet upon puppies, Circulation Res. 9:387, 1961. R. E., Katsutka, S., Vitale, J., and 7. Kleiger, Lown, B.: Effects of chronic depletion of potassium and magnesium upon the action of acetylstrophanthidin on the heart, Am. J. Cardiol. 17&20, 1966. 8. Kim. Y. W.. Andrews. C. E.. and Ruth. W. E.: Serum magnesium and cardiac arrhythmias with special reference to digitalis intoxication, Am. J. M. SC. 242:127, 1961. 9. Szekely, P., and Wynne, N. A.: Effects of magnesium on cardiac arrhythmias caused by digitalis, Clin. SC. 10:241, Ib.51. 10. Bellet. S.: Clinical disorders of the heart beat. ed. 1,‘Philadelphia. 19.53, Lea & Febiger, Pub: lishers, p, 215. B., Salzberg, H., Enselberg, C. D., and 11. Lown, Eston. R. E.: Interrelationship between potassium metabolism and digitalis-toxicity in- heart failure, Proc. Sot. Exper. Biol. & Med. 76:197, 1951. 12. Page, E., and Real, J. D.: Interrelationships between cardiac effects of ouabain, hypocalcemia and hyperkalemia, Circulation Res. 3:501, 195.5. J. J., Albertson, E. C., and Kondo, B.: 13. Sampson,
l~olume Number
14.
15.
16.
17.
18.
19.
79 1
Digitalis
The effect on man of potassium administration in relation to digitalis glycosides, AM. HEART J. 26:164, 1943. Lown, B., Weller, J. M., Wyatt, N., Hoigne, R., and Merrill, J. P.: Effects of alterations of body potassium on digitalis toxicity, J. Clin. Invest. 31:648, 1952. Jick, S., and Karsh, R.: The effect of calcium chelation on cardiac arrhythmias and conduction disturbances, Am. J. Cardiol. 4:287, 1959. Surawicz, B., MacDonald, M. G., Kaljot, V., and Bettinger, J. C.: Treatment of cardiac arrhythmias with salts of ethylenediamine tetraacetic acid (EDTA), AM. HEART J. 58:493, 19.59. Engbaek, L.: The pharmacologic action of magnesium ions with particular reference to the neuromuscular and cardiovascular systems, Pharmacol. Rev. 4:396, 1952. Bernstein, M. D.: Effect of intravenous magnesium on human heart, J. Lab. & Clin. Med. 25:131, 1939. Smith, P. K., Winkler, A. W., and Hoff, H. E.:
Appendix Table
22.
23.
24.
tables
Degrees of freedom
of variation
Between drugs Within drugs
Sums of squares
2 27 29
Total
5”
21.
Pharmacologic actions of parenterally administered salts, Anesthesiology 3:323, 1942. Moore, L. A., Hallman, E. T., and Sholl, L. B.: Cardiovascular and other lesions in calves fed diets low in magnesium, Arch. Path. 1:820, 1938. Greenberg, D. M., Anderson, C. E., and Tufts, E. V.: Pathological changes in the tissues of rats reared on diets low in magnesium, J. Biol. Chem. 114:43, 1936. Whang, R., and Welt, L. C.: Observations in experimental magnesium depletion, J. Clin. Invest. 42:305, 1963. Vitale, J. J., Nakamura, M., and Hegsted, D. M.: The effect of magnesium deficiency on oxidative phosphorylation, J. Biol. Chem. 228:573, 1957. Seta, K., Kleiger, R., Hellerstein, E. E., Lown, B., and Vitale, J. J.: Effect of potassium and magnesium deficiency on the electrocardiogram and plasma electrolytes of pure-bred beagles, Am. J. Cardiol. 17:516, 1966.
A. Sums of squares (toxicity)
Source
Table
20.
Mean square
!
1010.6487 27’18.7580
505.3244 100.6947
3729.4067
B.
1.67 1.73
44.8 59.3
1.13 0.94
57.9 32.0
0.79 0.99
30.5 57.9
22 23 24
1.66 1.15 1.00
55.1 45.0 38.5
0.85 0.68 0.53
50.0 43.2 30.2
0.84 0.45 0.44
37.2 24.5 37.1
26 27 17 18 28
1.69 2.34 1.11 1.45 1.33
34.5 44.0 45.9 46.7 60.2 __ 474.0 47.4
0.94 1.09 0.94 1.12 0.81
21.9 27.5 34.4 44.4 26.6
0.90 0.86 0.70 0.82 0.65
24.3 33.0 36.7 32.7 25.0
9.03 0.903
368.1 36.81
7.44 0.744
338.9 33.89
Total Means
67
toxicity and hypomagnesemia
15.13 1.513
--
_
31.6 -
31.6 1.053
1181 1181 393.67
68
Seller et 01.
Table C. Analysis
of covarinnce:
F-test; one-way cltrssijkation I
Deviation
; D.O.F.
regression
~ i
i sum of sq.
i
from
D.O. F.
ZC”
1
XA
~
ZAZ
Reduction
I Treatments Error
2 27 29
TSE
Statistical
A.
3.2958 2.0469 ___ 5.3427
57.7112 4.2221
1010.6487 2718.7580
61.9333
3729.4067
appendix*
To test whether there was a cumulative or carry-over effect from the acetyl strophanthidin infusions in the presence of constant magnesium, the data As-A, from Table I was used in a Wilcoxon Signed Rank test.
ArAz Ranks
2,
, 6
-8,
Aa-AS -1,
-11,
3, -5,
-2,
104.233
3011.4675 301.4183
150.709
tally significant at the 0.05 level. The hypothesis of no drop in acetyl strophanthidin tolerance has been rejected. C. To determine if the difference in means if the toxic amount of acetyl strophanthidin is directly related to the decrease in serum magnesium the
7,
-3,
5,
4
-8.3,-12.6,-1615
The appropriate statistic is T which is the absolute value of the sum of the negative ranks. The 0.05 cut-off point is 2, so that this value of T = 3 is not statistically significant at the 0.05 level. Hence the hypothesis of no cumulative effect has not been rejected at the 0.05 level. B. To test whether there was a drop in acetyl strophanthidin tolerance in the presence of hypomagnesemia, the data Ad-A8 from Table I was pooled with As-AZ from Table II. The Wilcoxon Signed Rank test was used again. The appropriate ranks are as follows: -7,
2710.0492
-9.6,+1.9,+2.2,-23.8,-14.6,-23.9,--11.0
A3-AZ-1.4,-12.8,-S.l,--1.8,
Ad-A3
26 28 2
+1.0,+2.7,0,+9.0,+13.8,-2.8,+7.4,+3.6 1,
AI-A,-9.1,
8.7088 ____ 717.9392
Mean square
4, -14,
-12,
-155,
-6,
-10,
-13
-9
In this instance, T = 7. The 0.05 cutoff point is 2.5, so that this is statisti*The foIlowing references were consulted: Wilcoxon. F., and Wilcox, R. A.: Some rapid approximate statistical procedures, Pearl River. N. Y., 1964, Lederie Laboratories Monograph. Snedecor. G. W., and Cochran, W. G.: Statistical methods, ed. 6, Ames. Iowa. 1967. Iowa State University Press.
question arises as to what effect the elimination of the magnesium removal as a concomitant variable will have on the difference in means in acetyl strophanthidin tolerance. We used the values of AZ, A,, and A4 in Table II pooled with the values of Ai, A?, and Aa in Table III (Table A). Fa, 27 = 5.0184 > 3.35 (significant at the 5 per cent level). This F value is significant. Next, an analysis of covariance was performed to eliminate the effect of the magnesium removal. The data are listed in Table B. Ff, 26 = 150.7092/104.233 = 1.446. This is not significant. The estimated slope of the regression is (4.221)/2.0469 = 2.0627. The adjusted means for the toxicity tolerance becomes for I: 47.4 II: 36.81 III: 33.89 -
2.0627 2.0627 2.0627
(1.513 (0.903 (0.744
-
1.053) 1.053) 1.053)
= 46.45 = 37.12 = 34.53.
Since these adjusted means are not significant, the removal of the magnesium effect has removed the differences in acetyl strophanthidin tolerance.