Journal of Nutritional Medicine (1994) 4, 169-177
CLINICAL EXPERIENCE
The Case for Intravenous Magnesium Treatment of Arterial
Disease in General Practice: Review of 34 Years of
Experience
S. E. BROWNE MB BCH
17 The Close, Wilmington, Dartford, Kent DA2 7ES, UK
Magnesium sulphate (MgSO4 ) in a 50% solution
was injected initially intramuscularly and later intravenously
into patients with peripheral vascular disease (including
gangrene, claudication, leg ulcers and thrombophlebitis), angina,
acute myocardial infarction (AMI), non-haemorrhagic cerebral
vascular disease and congestive cardiac failure. A powerful
vasodilator effect with marked flushing was noted after
intravenous (IV) injection of 4-12 mmol of magnesium (Mg) and
excellent therapeutic results were noted in all forms of arterial
disease. This technique of rapidly securing very high initial
blood levels of MgSO4 produces results in arterial
disease which cannot be equalled by oral vasodilators of
intramuscular (IM) or IV infusion therapy. It is suggested that
the most important action of MgSO4 in AMI is to open
up collateral circulation and relieve ischaemia thus reducing
infarct size and mortality rates. Prophylactic use of
MgSO4 and its effect on serum lipid, fibrinogen, urea
and creatinine levels are discussed.
Keywords: intravenous magnesium sulphate injections,
angina, acute myocardial infarction, non-haemorrhagic cerebral
vascular disease, claudication, serum lipids, fibrinogen,
congestive cardiac failure, early renal failure.
INTRODUCTION
Parenteral magnesium sulphate (MgSO4) has been used
[1, 2] in cardiovascular disease for the last 60 years.
Initially, no satisfactory explanation of its mode of action
emerged. To facilitate observation of its effects,
MgSO4 was given at first intramuscularly and then
intravenously in my practice in 1958 [3] to patients with
gangrene, leg ulcers, Raynaud's disease, chilblains and
intermittent claudication. A powerful vasodilator action
immediately became apparent; this action increased in potency
with increased initial blood concentrations, as had been seen
with arterial infusion of magnesium (Mg) in dogs [4]. Thus,
maximum therapeutic effect was, if necessary, obtained by rapidly
injecting 12 mmol of Mg; the intravenous (IV) route proved to be
the method of choice.
This vasodilator therapy has been highly effective especially
in coronary disease and non-haemorrhagic cerebrovascular disease
(NHCVD) [3, 5-8] but has been ignored by hospital workers until
the last few years. Mg has been demonstrated to be a calcium
antagonist in vascular muscle [9], at post-ganglionic sympathetic
nerve endings, in adrenal glands [10-12] and in blood clotting.
The possibility of using drugs to dilate coronary collateral and
peripheral vessels has been generally decried, but the conclusion
that it can occur has been inescapable from consideration of
patients with complete relief of severe angina and claudication
for 10 years or more after full courses of MgSO4. The
relief of anginal pain in elderly patients for long periods in my
practice drew attention to the possibility of improving the
coronary circulation in patients with congestive cardiac failure
(CCF) and a series of 30 patients is reported showing long-term
improvement after six injections.
MgSO4 injections have been shown to reduce the
level of serum lipids [2, 3, 13, 14]. The results of further
investigations are reported together with findings in the
treatment of angina, acute myocardial infarction (AMI), CCF,
NHCVD and peripheral vascular disease.
METHODS OF TREATMENT
Heparin was used initially with MgSO4 to protect
anginal patients against possible thrombosis [3, 5] during the
short period of hypotension often following IV MgSO4
injections. As Mg has an anticoagulant action [15] as well as a
fibrinolytic action [13], the use of heparin was discontinued
without any problems arising. However, in AMI, I now give 5000
units of IV heparin along with 8 mmol of Mg to make absolutely
certain that the sudden hypotension seen in some patients does
not lead to extension of the thrombus. Heparin appears to give
good pain relief when used with MgSO4 in AMI and a
trial of MgSO4 with and without heparin would be of
interest.
Normally, in angina, the initial dose of MgSO4 is 4
mmol given in an arm vein in about 10 seconds after 1 mmol has
been given fairly slowly to accustom the patient to the intense
feeling of warmth generated by IV Mg. If the patient is quite
happy, the dose is often increased to 8 mmol given on a further
five occasions either daily or weekly as is found convenient. In
AMI, I give 7 mmol MgSO4 with 5000 units of heparin in
about 15 seconds after an initial 1 mmol has been given more
slowly. Then, MgSO4 (8 mmol) is given daily for 2-3
days, or for longer if chest pain recurs. A further course of
three doses of 8 mmol is given after 2-3 weeks. In AMI, the dose
is reduced to 1 mmol or less, repeated at 15-min intervals, if
the blood pressure has fallen unduly (see later).
In NHCVD, I give a rest dose of 0.25 mmol before proceeding to
administer 4 mmol MgSO4. With careful selection of
patients, I have never had any problems but feel the treatment of
patients with NHCVD is ideally conducted in a hospital setting
with the use of modern diagnostic techniques. Obviously, the use
of MgSO4 is completely contra-indicated in cerebral
haemorrhage. In resistant cases of NHCVD, up to 12 mmol
MgSO4 have been injected in 20-30 seconds. The largest
daily dose given has been 16 mmol MgSO4. In angina,
repeated courses of MgSO4 are given if symptoms
recur.
Side-effects have not been a serious problem. Occasionally,
patients complain of headache and mild nausea and further
injections are than given more slowly or, rarely, intramuscularly
if the IV route is too upsetting. There is sometimes temporary
hypotension and patients are asked to rest in the horizontal
position for 5-10 min after injection. Patients with severe renal
failure will need special care to avoid undue rises in serum Mg
levels. Small and infrequent doses are indicated. Two patients
after treatment with IV MgSO4 and 5000 units of
heparin have developed subcutaneous haemorrhages.
RESULTS
Angina
A total of 126 patients with proven angina have been treated
with IV MgSO4 and 116 have either been completely
relieved of pain or markedly improved. Patients were considered
improved if they used significantly less glyceryl trinitrate and
could walk at least three times as far as previously at their
normal pace. Most patients were given six IV injections of
MgSO4 with a total dose of between 24 and 48 mmol of
Mg.
Case reports. A significant case [6] was that of a
man of 56 who after a major infarction in 1958 had very severe
angina which forced him to stop every 5 m when walking in cold
weather. He improved considerably on intramuscular (IM) therapy
but after a course of rapid bolus injections of 8 mmol of Mg
remained completely free from angina until his death from
carcinoma 8 years later. Subsequently, a number of similar
patients were completely relieved of severe anginal pain for 10
years or longer by IV therapy.
A male patient of 44 had a massive infarction followed by
severe angina in 1980. Angiogram revealed a huge ventricular
aneurysm 'with a very poor prognosis'. After a course of
MgSO4, he dramatically improved and had a normal
exercise test lasting 12.5 min. He had two further courses of
MgSO4 and had another normal exercise test in 1991 and
is well at present.
Two other patients with post-infarction ventricular aneurysm
also made excellent improvement. One had been offered a heart
transplant but markedly increased his exercise tolerance and more
than doubled his ejection fraction after weekly IV
MgSO4 and returned to a strenuous full-time job.
A patient of 66 had angina and claudication in the left leg
with a history of infarction and an ECG showing right bundle
branch block and ischaemic changes in the anterior and lateral
leads. The dorsalis pedis was not palpable in his left foot.
After repeated IV MgSO4 courses, he is free from
angina and claudication with a normal ECG and a strong pulse in
his left dorsalis pedis.
Myocardial Infarction
In a series of 59 patients treated immediately with 8 mmol of
IV Mg with or without heparin for AMI, chest pain was completely
or markedly improved in 24 patients before analgesics were
administered. Good recovery without any evidence of arrhythmias
occurred in all 59 patients in whom AMI was confirmed by ECG and
raised cardiac enzymes. The only patient with infarction and
arrhythmia seen had, on initial examination, a rapid and
irregular pulse of 160 plus with blood pressure of 45 systolic.
After IV administration of 1 mmol of Mg, the blood pressure
quickly improved to 120/80 and the pulse became regular with a
rate of 120 and the patient made a good recovery with further IV
therapy.
Cardiac Failure
In a series of 30 patients [6] with mild to moderate CCF but
without anginal symptoms, treated with IV MgSO4, 24
showed marked long-term improvement and at one year follow-up 20
patients had maintained their improved status. Of 13 similar
patients previously reported [3], 11 were improved in varying
degrees.
Case report. A woman with CCF and gross hepatic
enlargement showed dramatic improvement in exercise tolerance and
complete resolution of liver enlargement.
Cerebral Vascular Disease
Eighteen out of 34 patients [3, 5, 6, 8] with NHCVD showed
marked improvement after IV MgSO4, often with dramatic
recovery of function, always occurring within 1-2 min of an
injection.
Case reports. A man of 60 with severe paralysis of
the left arm was able to move his arm with full power 1 min after
IV injection of 8 mmol of Mg.
A woman of 73 was admitted on three occasions to the local GP
hospital with complete hemiplegia and aphasia and on the third
occasion was in status epilepticus. On each occasion, she made a
full recovery and walked out of hospital after 4 days of IV
MgSO4 injections.
A female of 57 had gradual onset of marked weakness and loss
of sensation in her left arm, hand, leg and foot. She attended a
professorial medical clinic for 3 months without improvement.
Treatment was begun with oral vasodilators which were ineffective
and then IM therapy with MgSO4 produced slight
improvement. After rapid injection of 10 mmol of Mg, her symptoms
completely resolved for 12 h and then relapsed but full recovery
occurred after a short course of IV therapy. Her CCF was much
improved concurrently. This patient reaffirmed the importance of
rapid IV injection and also showed that full recovery is possible
from a stroke even after a considerable period of time has
elapsed. Presumable, partial ischaemia affected function without
permanently damaging brain tissue.
A woman of 31 on oral contraceptives suffering from cerebral
thrombosis presented with moderate right-sided hemiplegia, marked
right-sided sensory loss, dysphasia and right homonymous
hemianopia which were considered to be due to thrombosis of the
left middle cerebral artery. After 3 weeks in hospital, she was
discharged unimproved in any respect. After six injections each
of 8 mmol of IV Mg given at intervals of 2 or 3 days, recovery
was almost complete. Each stage of recovery was closely related
to each injection with a marked initial response within 1.5 min
followed by further improvement observed over a period of 2-3 h.
Within 1.5 min of the first injection the patient reported
'tingling feelings' in the right arm and leg and demonstrated
marked improvement in touch and pain sensation. The second and
third injections secured an immediate increase in power and
sensation in the right arm and leg, and the fourth a further
increase, demonstrated dramatically by improved walking and
recovery of her ability to feed and change her baby from that
point without assistance from her husband. She remained well
apart from minor partial seizures which have responded to IV
MgSO4 and Carbamazepine and Sodium Valproate. One
patient with retinal vessel thrombosis, confirmed at a consultant
clinic, made a complete recovery after treatment with
MgSO4.
Peripheral Vascular Disease
In a soft water area [3], 6 out of 7 patients with
claudication were markedly improved by IV or IM MgSO4.
In a hard water area, 14 out of 25 patients with claudication
showed marked improvement after IV MgSO4, and of 8
patients with leg ulcers 5 healed quickly after failing to
respond to all other measures over extended periods. One patient
with spina bifida had a chronic trophic foot ulcer which
completely healed in 4 weeks. Seventeen patients with superficial
thrombo-phlebitis were free of pain, tenderness and inflammation
with only residual induration observable after 2 weeks of
treatment, a further seven were fully recovered after 3-4 weeks
of treatment with one patient unimproved. Four patients with deep
vein thrombosis showed rapid improvement on IV MgSO4
given in addition to anticoagulant therapy.
Case report. Two elderly men [3] with incipient
gangrene and severe pain and swelling of heels and toes rapidly
improved on regular IM doses of 4 mmol of Mg. After 18 months
their feet were much warmer and free from pain and swelling.
Serum Lipids, Fibrinogen, Urea and Creatinine Levels
In a soft water area [3] MgSO4 therapy of 12
patients with an average serum cholesterol level of 9.7 mmol
1-1 produced an average fall of 23% in 7 patients with
no change in 5. In a hard water area, IV MgSO4 of 36
patients with an average cholesterol level of 6.84 mmol
1-1 resulted in 23 patients showing a fall in
cholesterol and 13 a rise, while 15 showed a rise in high-density
lipoprotein and 21 a fall. Changes in triglyceride levels were
equally divided. Forty patients showed a fall in fibrinogen
levels and 8 patients showed a rise after MgSO4
treatment with 4 patients unaffected. In 22 patients with early
renal disease, serum creatinine and urea levels were reduced in
16 patients with a rise in 3 and no change in 3 others.
DISCUSSION
Angina and Claudication
Parenteral MgSO4 was found to be effective in
angina and in AMI by a number of early workers [16-18]. The best
results were obtained with IV therapy. While Agranat [19]
reported only 25 out of 50 patients with angina improved by IM
therapy, Perlia [20] found 77 out of 79 patients improved after
IV MgSO4.
It has been noted [21] that calcium and magnesium were
decreased in coronary arteries in soft water areas in males under
40 and decreases in older males may have been concealed by the
presence of magnesium in atheromatous plaques. My impression is
that results in claudication (6 out of 7) were significantly
better in a soft water area [3] than in a hard water area (14 out
of 25) and this may reflect a difference in arterial rigidity and
capacity for dilation, which may also contribute to the reported
varying results of Mg therapy in AMI.
I have previously reported [3] an experiment with
intra-femoral injection of MgSO4 in claudication which
was only partly successful because of heat discomfort in the
femoral artery. In view of the striking benefits noted with
intra-arterial perfusion of thymoxamine in occlusive arterial
disease of the lower limbs [22], further work seems indicated in
a hospital setting with MgSO4, as 2 patients treated
recently by intra-femoral injections have had complete relief of
claudication. As access to the femoral artery is difficult in
patients with gross femoral artery disease, rapid injection of 6
ml of IV MgSO4 may be almost as effective.
In a series of patients with angina [5], 3 patients failed to
respond to MgSO4 after relapsing and 2 of them died
within 3 months. Another patient treated later died 4 months
after unsuccessful treatment. In consequence, it was decided that
in similar circumstances patients under 70 would be referred for
urgent coronary arteriography in the belief that coronary disease
in two or more vessels was present preventing any increase in
collateral circulation, and since then this has been confirmed in
almost every patient referred [6]. This finding supports the
conclusion that the only explanation for the complete recovery of
patients with severe angina after treatment for periods of 10
years or more must be that collateral circulation has been
extensively opened up which obviously cannot occur if severe
coronary disease is present. Mg therapy is therefore of value in
indicating patients who need bypass grafts, and dilating
collaterals with IV MgSO4 before surgery may improve
the run-off from grafts.
Myocardial Infarction and Arrhythmias
The absence of arrhythmias in 59 patients with AMI treated
with IV MgSO4 highlights the importance of early bolus
therapy. Malkiel-Shapiro [16] reported the treatment of 64
patient with AMI with IM MgSO4 with only one death. He
also emphasized the importance of early treatment. Parsons [13]
reported one death in 33 patients with AMI treated with IM
MgSO4.
In the prevention or treatment of arrhythmias after AMI, Mg
acts in a variety of ways, the most important action being its
vasodilating effects which improves the blood supply to ischaemic
areas and reduces infarct size. Mg also has a direct depressant
action on heart conductivity, an important role in potassium
metabolism and a calcium-blocking action, which includes the
prevention of catecholamine release from post-ganglionic
sympathetic nerve endings and adrenal glands [10, 11, 23].
Seifter [24] has found that Mg, ATP and catecholamines form
complexes which are much less potent than the original
catecholamines. Both modes of action reduce the mobilization of
free fatty acids by catecholamines [25]. Significantly more
deaths from serious arrhythmias occur in AMI patients with high
serum levels of free fatty acids [26]. Mg also has a fibrinolytic
action [13], prolongs clotting time, delays peak thrombin time
[15], slows down platelet clumping [27] and appears to reduce
fibrinogen levels, all of which may prevent development or
extension of an infarct. Significant Mg deficiency in heart
muscle [28, 17, 29] after death from AMI has been well
documented, as has the use of Mg salts to control arrhythmias
[30, 31].
Recent trials of Mg infusion [32-34] in AMI have shown
reduction of mortality rates ranging from one-third to two-thirds
and some have shown reduction in arrhythmias. Rasmussen [32]
believed the beneficial results of Mg infusion in AMI were due to
its anti-arrhythmic action. In my view, this is much less
important than the vasodilator action which opens collateral
circulation and reduces myocardial damage. This is confirmed by
Rasmussen's own results. Of 136 patients treated with Mg, only 56
actually developed an infarction compared with 74 in the placebo
group.
In a recent trial [35], general practitioners gave
Anistreptase to patients when first seen with suspected AMI and
reduced the mortality rate by 50% compared with the 25% reduction
usually achieved in hospital trials. If a similar approach were
adopted with IV MgSO4, the reduction in mortality
rates could be considerably increased. The frequent relief of
pain and the improved general condition of patients given
MgSO4 when first seen by myself suggests that
myocardial ischaemia is relieved at a vitally important early
stage. Some patients do not progress to AMI as shown later by
normal enzyme levels while those who do have minimal myocardial
damage.
In some patients with AMI, IV MgSO4 can produce a
fall in blood pressure which, if not excessive, may be more
beneficial than harmful. In severe cardiogenic shock, the dosage
of Mg has been reduced from 8 mmol to 1 mmol or even 0.20 mmol
repeated at 15-min intervals with blood pressure monitoring until
4 mmol have been given [5]. Singh [36] has reported dramatic
improvement in severe shock using an IV vasodilator. Further
studies are required of MgSO4 administration in
cardiogenic shock. The patient reported with blood pressure of 45
systolic made a rapid recovery after 1 mmol of Mg was given.
Patients in high-risk categories for coronary disease would
logically be in less danger during actual AMI if collateral
circulation were previously maximized. High-risk patients in my
practice are therefore offered a prophylactic course of
MgSO4, as are all patients after suffering myocardial
infarction. Routine MgSO4 therapy after AMI produces
considerable improvement with respect to angina and exercise
tolerance [3], and did so in all 7 post-infarction patients in
one series of 30 patients with angina.
Cerebral Vascular Disease
Only 34 patients with NHCVD have been treated because of the
importance of being certain of the diagnosis. Patients with
hypertension and dramatic onset of symptoms have not been
treated, as MgSO4 is obviously contra-indicated in
cerebral haemorrhage and consequently few cases have been
treated. With modern methods of diagnosis, hospital patients with
cerebral thrombosis, embolus or cerebral vascular insufficiency
could easily be diagnosed and treated.
In view of the complete resolution of retinal vessel
thrombosis in the only patient treated, it is interesting to note
that Malkiel-Shapiro [2] reported marked improvement in 2
patients with hypertensive retinopathy following treatment with
MgSO4.
HEART DISEASE AND WATER SUPPLIES
In soft water areas, the heart muscle of people dying after
accidents has been shown to have significantly lower
concentrations of Mg [37] than similar samples from people in a
hard water area. Serum Mg levels were similar in residents of
hard and soft water areas [38] but Seelig has concluded that
serum Mg levels are an unreliable indicator of Mg status [39].
The low level of Mg in heart muscle in soft water areas is
significant when one considers the well-known fact of an
increased incidence of sudden death from heart disease [40] in
those areas; it has been suggested frequently that lack of Mg in
soft drinking water [39] may be the vital factor concerned. I
advise anginal patients in soft water areas to take at least one
Mg hydroxide tablet daily and patients in hard water areas to do
the same, or at least drink some unboiled water each day. As Mg
balance may be very critically poised with modern diets [41],
even small additions of Mg to the diet may be crucial in
preventing Mg deficiency and hence the possible development of
arrhythmias and sudden death during infarction.
Enough attention has not been paid to the higher incidence of
heart disease and hypertension in the soft water areas of
Scotland, Northern Ireland and Northern England. Morris [42]
reported high negative correlations between cardiovascular
disease and water hardness in England and Wales. Dyckner [43] and
many others have demonstrated falls in blood pressure when Mg
supplements were added to patients' diets. Stitt [44] found that
there was a significantly higher level of blood pressure between
the ages of 50 and 65 in residents of a soft water area as
compared with those in a hard water area.
SERUM LIPIDS
Parsons [13] treated 50 patients with IM MgSO4 of
whom 39 showed a fall in cholesterol levels and 11 a rise; 32
exhibited a rise in fibrinolytic activity and 18 a fall, while 42
had a fall in plasmin inhibition and 8 a rise. There was no
correlation between serum Mg and cholesterol levels. I found that
Mg reduced serum fibrinogen in a majority of patients. Savenkov
[45] found a fall in cholesterol levels in 29 out of 41 patients
treated with Mg with no change in 9 and a rise in 3. However,
epidemiological studies of hard and soft water cities report
varying results in relating hardness of water supplies [39, 44,
46, 47] to serum cholesterol levels, nor as a clear pattern
emerged from conflicting studies of serum Mg and cholesterol
levels in healthy and atherosclerotic patients [39] and in racial
groups with differing rates of heart disease [39, 48]. It may be
that some patients have satisfactory Mg balance and so control
their serum lipids more effectively through the calcium-blocking
action of Mg in the adrenal glands and post ganglionic
sympathetic nerve endings [10, 11], thus preventing the release
of catecholamines which mobilize free fatty acids from adipose
tissue [24]. Excessive mobilization may possible lead to
increased body production of cholesterol and to higher serum
levels. I found that Mg therapy appeared to lower serum
cholesterol more effectively in a soft water area where total
body Mg is more likely to be reduced.
In one study [44], non-smokers living in hard water areas were
reported to have lower serum cholesterol levels than those in
soft water areas, but smokers, ex-smokers, cigar and pipe smokers
did not show any significant difference. Nicotine promotes
catecholamine release in the adrenals and at sympathetic nerve
endings [25] and appears to prevent the cholesterol-lowering
effect noted in non-smokers which could possibly be mediated by
higher Mg status [39] in residents of hard water areas.
CONCLUSION
The successful use of IV MgSO4 as a powerful
calcium-blocking vasodilator is described in angina, AMI, cardiac
failure, NHCVD and peripheral vascular disease. IV
MgSO4 appears to relieve completely or markedly
improve all patients with angina unless severe double or triple
vessel disease is present. It is suggested that the powerful
vasodilating action of MgSO4 in coronary disease opens
permanently collateral circulation in the heart. Routine early
MgSO4 therapy in AMI is doubly effective in that it
appears to prevent arrhythmias as well as increasing collateral
circulation, often with immediate relief of chest pain and
reduction of infarct size. It also offers an effective treatment
for NHCVD. Mg therapy has great therapeutic potential in arterial
disease and has the prime advantages of being cheap and free from
unwelcome side-effects.
ACKNOWLEDGEMENTS
I would like to record my gratitude to Dr. Thoruson, former
editor of The Practitioner, and Dr. Peter Nixon, both of
whom have encouraged my work.
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