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The action of calcium on the human electrocardiogram
THE
ACTION
OF CALCIUM
ON THE
HUMAN
ELECTROCARDIOGRAM
NORMAX E. CLARKE, M.D. DETROIT,
MICH.
T
HE continued response of heart muscle to stimuli &pen& upon calcium, and excessive amounts of calcium in a perfusion medium will completely suspend relaxation. Billigheimer’ found that calcium makes the heart’s contractile elements more powerful, i.e., that it has an inotropic and also perhaps a bathmotropic effect. After having performed experiments on animals, Kolm and Pick2 believed that calcium paralyzed the auricles and increased the irritability of the ventricles. The cardiotonic action of calcium was investigated by Danielopolu, et a1.,3 who thought that the diuresis which followed calcium therapy resulted from the action of the drug on the heart, but Loewenberg* regarded the diuretic and cardiac effects as independent. We have studied the action of calcium on the human heart with the electrocardiograph-a method used by Berliner.” A-2 per cent solution of calcium chloride was used in most of our experiments, but in some a 70 per cent solution was used. From 45 to 75 grains of the drug were given intravenously over a period of three to twenty-one minutes. The rapidity of administration, or the concentration of the drug in the blood stream, determines t,he effect. One to four grams of calcium chloride were given intravenously by Ameuillc and Rista in treating abdominal tuberculosis. The number of our experiments was limited because of the risk entailed by the doses we used, the difficult,y of finding human subjects who were willing to undergo such experimentation, and our own reluctance to subject many to such a procedure. A fairly constant train of symptoms was observed. The patients complained of intense flushing, or heat, palpitat,ion increasing in intensity, a sense of oppression in breathing, nausea, a metallic taste, profuse perspirat.ion, marked dFspnea, occasional vomiting, faintness, weakness, and a feeling of pressure over the upper sternum, with a dull general headache. Some of these symptoms are to be explained by the dynamic action of rapid intravenous administration. Reports vary as to the effect of calcium on the blood pressure. We found, uniformly, an elevation of the systolic, and usually a depression of the diastolic, levels. These changes were transient ; normal pressures Keceiveti
for
Ix~hiicwtion
Jan.
1, 1941. B67
368
Fig.
THE
l.-Case
1.
AMERI(‘.ZS
lZlectrocardiograrr1 a decrease
Fig. 2A.-Case 3. The heart occasmnally are inverted : and auricular extrasystoles, appear. arrhythmia is more pronounced.
shows in the
HEART
.JOI’RSAIA
sinus arrhythmia, size of the P waves.
slowing
of the
rate,
and
rate is decreased; the P waves become smaller ventricular extrasystoles of large voltage, and The size of the R waves is much increased; and the pacemaker shifts to a lower level.
and also sinus
returned within thirty minutes to one hour, ant1 the maximum fall occurred within a few minutes after the administration of calcium was stopped. C.\YF, I REI’ORTS
(I.~sIc 1.-A male physician, aged 34 years, who was in good health and had a normal heart, was the subjecst of our first and least satisfactory experiment. A t.ot.al of 40 grains of calcium rhloride in a 2 per caent solution was administered intravenously within twenty-one minutes. The appearance of palpitation, faintness, nausea, and vomiting required the discontinuanre of the drug. There was no diuresis. The initial blood pressure was 135/80. The systolic readings during t.he administration of the rxlcium were 145 ant1 11i5, and the diastolic, 70 and fi5, mm. Hg. The systolic pressure was 145, and the diastolic, 75, mm. Hg thirty minutes after the administration of calcium was stopped; the readings were normal within one hour. These rhanges were probably exaggerated by the anxiety assoc~iated with the proce#lure. ,1 continuous clrctroc~nrdiographic of ralcium administration (Fig.
recaortl
(Lead
I)
was
made
during
the
I’eriod
1).
wig. BB.---Case 3. With further administration of calcium, sinoauricular and block are present. Most of the P waves become inverted, and all are decreased size. The P-P intervals are shorter, and the apices of the R waves are notched. independent ventricular rhythm intervenes: the P waves are still present, with ventricular response to the supraventricular stimulus casional
received
was
64.5
a man,
grains
aged
of
40 years,
in An oc-
whose general health was good. This by vein within eleven minutes. A 2 per cent solution was used. When 22.5 grains had been given, he complained of a metallic taste in his mouth and began to perspire profusely. There was no diuresis. CASE
patient
Z.-This
A-V
calcium
chloride
370
THX
The normal, the systolic
resting readings
Moo11 were
AMEHICAK
HEART
pressure wal; 95/G. 115, 125, 130, and
JOlJKN.\I>
During 135, and
the injection the diastolic,
of the calriuru 65, 65, ti-i, and
70 mm. Hg. Within twent,y minutes after the withdrawal of the needle from the The electrocardiographic alterations were more vein the blood pressure was 110/70. pronounced than those shown by the first patient. The outlines were more distinct and the rate was decreased, but sinus arrhythmia was not so evident. The P Waves were decreased in size, and became inverted, with a sharpening of their apices.
Fig.
ZC.-Case
much
3.
The heart incratsed,
rate becomw and all evi
more of
rapid auricular
: the
size
activity
of the K waves dis;kPPears.
rem:tinS
CASE 0.-This ” patient, aged 45 years, bad a chronic discharging sinus on his left leg. The cardiovascular examination showed nothing abnormal. He was given 250 e.c. of a 2 per cent solution of calcium chloride (75 grains) wit.hin nine minutes There were few symptoms. The tracings are chest leads; by the intravenous route. Lead II was used for the continuous tracing. The normal, resting blood pressure During the administration of the calcium the systolic readings were was 145/90.
150, 1.50, 180, and 175, and the diastolic, in the same sequence, were 85, SO, 80, and 75 mm. Hg. The st,riking changes in his electrocardiograms are shown in Fig. 28, H, c, n.
In Case 3 the heart rate decreased; sinus arrhythmia appeared; the pacemaker was displaced to a lower level; and transient partial and complete heart block was produced. These changes resemble those produced by vagal stimulation. It was observed by Hoff and Nahum,7 in their experimental work with rabbits, that suppression of vagal action by atropine before the intravenous injection of calcium prevented A-V delay and auricular fibrillation.
Fig.
some rhythm same
“I).--Case 3. In the first half of this upright. and others are inverted. In resumes, with a short period of bigeminal form as those in thr par’or.ysm.
are
series the P waves are again evident: the last half, the idiopathic ventricular rhythm : the extrasystoles are of the
That there is an action on the ventricular muscle seems probable ; estrasystoles, usually of large voltage, and series of extrasystoles or paroxysmal ventricular tachycardia occur. This type of extrasystole persists when the vagus is suppressed by atropine, according to Hoff and Nahum,’ which suggests that increased ventricular excitability is produced by dir&t calcium action on the ventricular muscle.
In an effort to further differentiate the vagal and direct, muscle action of calcium chloride, we administered the drug to a patient, with auricular fibrillation. CASE 4.-A man, failure with dependent fibrillation, ad mitd to t,hc administration intmvmouslp, within
agrcl 47 years, with rheumntir heart clisease, had had heart edemx, for five months. Hr hat1 cardiw enlargement, auricula~ Stenosis. He 11x1 rwrived a snxtll amount of dipjtalis previous of 13 grains of calcium rhloritlr in :t 10 per wut WhItion. three minutes.
Fig. I.-Case 4. Lead travenous administration electrocardiogram.
I was used. This continuous of the calcium solution, but
record was no change
taken during is noted in
inthe
In this single experiment, the calcium had no detectable effect on the electrocardiogram, i.e., the cllanges which were noted in cases of sinus rhythm did not occur in the A single example (lees not permit conclusions. presence of auricular fibrillation. SUMMARY
The intravenous therapeutic use of calcium has advantages and henefits, but carries definite danger. Calcium produces changes in t,he hunlan electrocardiogram which are progressive and depend upon the calcium concentration in the blood stream.
The earliest and vagus-like actions arc bradycurdia, sinus arrhyt,hmia, shifting of the pacemaker, and various degrees of heart block, Calcium may. act directly upon the ventricular muscle, increasing its excitability, and producing foci of idiopathic ventricular rhythm and ventricular ext,rasystoles of large and unusual form. The blood pressure was alt,ered ; the systolic level was raised, and t,hc diastolic usually was depressed. Accompanying psychic fact,ors and symptoms, such as nausea and chest oppression, could account for some of the change. We observed no diuresis from calcium administration, and t,he effects on the heart itself were very transitory. In the single .case of auricular fibrillation the intravenous administrat.ion of calcium had no effect on the eleet~rocardiogram. REFERENCES 1. Billigheimer, E. : Vergleiehende Untersuchungen iiber die Wirkung und Wirkungweise des Calciums und der Digitalis, Ztschr. f. klin. Med. 100: 411, 1924. iiber die Bedeutung des Kaliums fiir die Selh2. Kolm, R., and Pick, E. P.: steurung des Herzens, Arch. f. d. ges. Physiol. 185: 235, 1920. 3. Danielopolu, D., Draganesco, S., and Copaceanu, P.: Les sels de calcium dans l’asystolie, Presse m8d. 30: 413, 1922. L ‘action cardiotonique et 1 ‘action diuretique du chlorure de 4. Loewenberg, B.: calcium, Ann. de m8d. 13: 172, 1923. Effect of Calcium Injections on the Human Heart, Am. J. M. SC. 5. Berliner, K.: 191: 117, 1936. Les injections intraveineuses de chlorure de cal6. Ameuille, P., and Rist, E.: cium, Bull. et m6m. Sac. m6d. d. Hap. de Paris 48: 531, 1924. An Analysis of the Cardiac Irregularities Pro7. Hoff, H. E., and Nahum, L. H.: duced by Calcium, and Their Prevention by Sodium Amytal, J. Pharmacol. & Exper. Therap. 60: 425, 1937.
ACTION
OF CALCIUM
ON THE
HUMAN
ELECTROCARDIOGRAM
NORMAX E. CLARKE, M.D. DETROIT,
MICH.
T
HE continued response of heart muscle to stimuli &pen& upon calcium, and excessive amounts of calcium in a perfusion medium will completely suspend relaxation. Billigheimer’ found that calcium makes the heart’s contractile elements more powerful, i.e., that it has an inotropic and also perhaps a bathmotropic effect. After having performed experiments on animals, Kolm and Pick2 believed that calcium paralyzed the auricles and increased the irritability of the ventricles. The cardiotonic action of calcium was investigated by Danielopolu, et a1.,3 who thought that the diuresis which followed calcium therapy resulted from the action of the drug on the heart, but Loewenberg* regarded the diuretic and cardiac effects as independent. We have studied the action of calcium on the human heart with the electrocardiograph-a method used by Berliner.” A-2 per cent solution of calcium chloride was used in most of our experiments, but in some a 70 per cent solution was used. From 45 to 75 grains of the drug were given intravenously over a period of three to twenty-one minutes. The rapidity of administration, or the concentration of the drug in the blood stream, determines t,he effect. One to four grams of calcium chloride were given intravenously by Ameuillc and Rista in treating abdominal tuberculosis. The number of our experiments was limited because of the risk entailed by the doses we used, the difficult,y of finding human subjects who were willing to undergo such experimentation, and our own reluctance to subject many to such a procedure. A fairly constant train of symptoms was observed. The patients complained of intense flushing, or heat, palpitat,ion increasing in intensity, a sense of oppression in breathing, nausea, a metallic taste, profuse perspirat.ion, marked dFspnea, occasional vomiting, faintness, weakness, and a feeling of pressure over the upper sternum, with a dull general headache. Some of these symptoms are to be explained by the dynamic action of rapid intravenous administration. Reports vary as to the effect of calcium on the blood pressure. We found, uniformly, an elevation of the systolic, and usually a depression of the diastolic, levels. These changes were transient ; normal pressures Keceiveti
for
Ix~hiicwtion
Jan.
1, 1941. B67
368
Fig.
THE
l.-Case
1.
AMERI(‘.ZS
lZlectrocardiograrr1 a decrease
Fig. 2A.-Case 3. The heart occasmnally are inverted : and auricular extrasystoles, appear. arrhythmia is more pronounced.
shows in the
HEART
.JOI’RSAIA
sinus arrhythmia, size of the P waves.
slowing
of the
rate,
and
rate is decreased; the P waves become smaller ventricular extrasystoles of large voltage, and The size of the R waves is much increased; and the pacemaker shifts to a lower level.
and also sinus
returned within thirty minutes to one hour, ant1 the maximum fall occurred within a few minutes after the administration of calcium was stopped. C.\YF, I REI’ORTS
(I.~sIc 1.-A male physician, aged 34 years, who was in good health and had a normal heart, was the subjecst of our first and least satisfactory experiment. A t.ot.al of 40 grains of calcium rhloride in a 2 per caent solution was administered intravenously within twenty-one minutes. The appearance of palpitation, faintness, nausea, and vomiting required the discontinuanre of the drug. There was no diuresis. The initial blood pressure was 135/80. The systolic readings during t.he administration of the rxlcium were 145 ant1 11i5, and the diastolic, 70 and fi5, mm. Hg. The systolic pressure was 145, and the diastolic, 75, mm. Hg thirty minutes after the administration of calcium was stopped; the readings were normal within one hour. These rhanges were probably exaggerated by the anxiety assoc~iated with the proce#lure. ,1 continuous clrctroc~nrdiographic of ralcium administration (Fig.
recaortl
(Lead
I)
was
made
during
the
I’eriod
1).
wig. BB.---Case 3. With further administration of calcium, sinoauricular and block are present. Most of the P waves become inverted, and all are decreased size. The P-P intervals are shorter, and the apices of the R waves are notched. independent ventricular rhythm intervenes: the P waves are still present, with ventricular response to the supraventricular stimulus casional
received
was
64.5
a man,
grains
aged
of
40 years,
in An oc-
whose general health was good. This by vein within eleven minutes. A 2 per cent solution was used. When 22.5 grains had been given, he complained of a metallic taste in his mouth and began to perspire profusely. There was no diuresis. CASE
patient
Z.-This
A-V
calcium
chloride
370
THX
The normal, the systolic
resting readings
Moo11 were
AMEHICAK
HEART
pressure wal; 95/G. 115, 125, 130, and
JOlJKN.\I>
During 135, and
the injection the diastolic,
of the calriuru 65, 65, ti-i, and
70 mm. Hg. Within twent,y minutes after the withdrawal of the needle from the The electrocardiographic alterations were more vein the blood pressure was 110/70. pronounced than those shown by the first patient. The outlines were more distinct and the rate was decreased, but sinus arrhythmia was not so evident. The P Waves were decreased in size, and became inverted, with a sharpening of their apices.
Fig.
ZC.-Case
much
3.
The heart incratsed,
rate becomw and all evi
more of
rapid auricular
: the
size
activity
of the K waves dis;kPPears.
rem:tinS
CASE 0.-This ” patient, aged 45 years, bad a chronic discharging sinus on his left leg. The cardiovascular examination showed nothing abnormal. He was given 250 e.c. of a 2 per cent solution of calcium chloride (75 grains) wit.hin nine minutes There were few symptoms. The tracings are chest leads; by the intravenous route. Lead II was used for the continuous tracing. The normal, resting blood pressure During the administration of the calcium the systolic readings were was 145/90.
150, 1.50, 180, and 175, and the diastolic, in the same sequence, were 85, SO, 80, and 75 mm. Hg. The st,riking changes in his electrocardiograms are shown in Fig. 28, H, c, n.
In Case 3 the heart rate decreased; sinus arrhythmia appeared; the pacemaker was displaced to a lower level; and transient partial and complete heart block was produced. These changes resemble those produced by vagal stimulation. It was observed by Hoff and Nahum,7 in their experimental work with rabbits, that suppression of vagal action by atropine before the intravenous injection of calcium prevented A-V delay and auricular fibrillation.
Fig.
some rhythm same
“I).--Case 3. In the first half of this upright. and others are inverted. In resumes, with a short period of bigeminal form as those in thr par’or.ysm.
are
series the P waves are again evident: the last half, the idiopathic ventricular rhythm : the extrasystoles are of the
That there is an action on the ventricular muscle seems probable ; estrasystoles, usually of large voltage, and series of extrasystoles or paroxysmal ventricular tachycardia occur. This type of extrasystole persists when the vagus is suppressed by atropine, according to Hoff and Nahum,’ which suggests that increased ventricular excitability is produced by dir&t calcium action on the ventricular muscle.
In an effort to further differentiate the vagal and direct, muscle action of calcium chloride, we administered the drug to a patient, with auricular fibrillation. CASE 4.-A man, failure with dependent fibrillation, ad mitd to t,hc administration intmvmouslp, within
agrcl 47 years, with rheumntir heart clisease, had had heart edemx, for five months. Hr hat1 cardiw enlargement, auricula~ Stenosis. He 11x1 rwrived a snxtll amount of dipjtalis previous of 13 grains of calcium rhloritlr in :t 10 per wut WhItion. three minutes.
Fig. I.-Case 4. Lead travenous administration electrocardiogram.
I was used. This continuous of the calcium solution, but
record was no change
taken during is noted in
inthe
In this single experiment, the calcium had no detectable effect on the electrocardiogram, i.e., the cllanges which were noted in cases of sinus rhythm did not occur in the A single example (lees not permit conclusions. presence of auricular fibrillation. SUMMARY
The intravenous therapeutic use of calcium has advantages and henefits, but carries definite danger. Calcium produces changes in t,he hunlan electrocardiogram which are progressive and depend upon the calcium concentration in the blood stream.
The earliest and vagus-like actions arc bradycurdia, sinus arrhyt,hmia, shifting of the pacemaker, and various degrees of heart block, Calcium may. act directly upon the ventricular muscle, increasing its excitability, and producing foci of idiopathic ventricular rhythm and ventricular ext,rasystoles of large and unusual form. The blood pressure was alt,ered ; the systolic level was raised, and t,hc diastolic usually was depressed. Accompanying psychic fact,ors and symptoms, such as nausea and chest oppression, could account for some of the change. We observed no diuresis from calcium administration, and t,he effects on the heart itself were very transitory. In the single .case of auricular fibrillation the intravenous administrat.ion of calcium had no effect on the eleet~rocardiogram. REFERENCES 1. Billigheimer, E. : Vergleiehende Untersuchungen iiber die Wirkung und Wirkungweise des Calciums und der Digitalis, Ztschr. f. klin. Med. 100: 411, 1924. iiber die Bedeutung des Kaliums fiir die Selh2. Kolm, R., and Pick, E. P.: steurung des Herzens, Arch. f. d. ges. Physiol. 185: 235, 1920. 3. Danielopolu, D., Draganesco, S., and Copaceanu, P.: Les sels de calcium dans l’asystolie, Presse m8d. 30: 413, 1922. L ‘action cardiotonique et 1 ‘action diuretique du chlorure de 4. Loewenberg, B.: calcium, Ann. de m8d. 13: 172, 1923. Effect of Calcium Injections on the Human Heart, Am. J. M. SC. 5. Berliner, K.: 191: 117, 1936. Les injections intraveineuses de chlorure de cal6. Ameuille, P., and Rist, E.: cium, Bull. et m6m. Sac. m6d. d. Hap. de Paris 48: 531, 1924. An Analysis of the Cardiac Irregularities Pro7. Hoff, H. E., and Nahum, L. H.: duced by Calcium, and Their Prevention by Sodium Amytal, J. Pharmacol. & Exper. Therap. 60: 425, 1937.