The Case for Intravenous Magnesium Treatment of Arterial Disease in General Prac

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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

http://www.mgwater.com/browne01.shtml

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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