Does Intravenous Magnesium, given early in Acute Stroke improve outcome?

[Guest guest]

Does Intravenous Magnesium, given early in Acute Stroke improve

outcome? JoAnn Guest

Oct 25, 2004 12:09 PDT

 

Does intravenous magnesium, given early in acute stroke improve

outcome for patients?

 

http://www.neurosurgery-neff.com/IMAGES.html

 

Intravenous magnesium sulphate is neuroprotective in preclinical

models of stroke, and preliminary clinical data indicate that it is

safe, well-tolerated and possibly beneficial in stroke patients.

 

IMAGES is a randomized, double-blind, placebo-controlled, multi-

center collaborative trial designed to test the efficacy of

magnesium sulphate given within 12 hours of onset of clinically

diagnosed acute stroke.

 

Any conscious patient (older than 18 and previously independent)

presenting with acute stroke symptoms including unilateral limb

weakness, lasting

longer than one hour, would be eligible for this study.

 

Treatment must be initiated within a 12 hour time window from the

onset of the stroke.

Eligible consented patients are randomized by administration of

previously coded solutions prepared and consecutively labelled.

Solutions will be identified by code number, which will be kept in

the pharmacy in a secure area.

 

Treatment is given as a 15 minute loading dose infusion followed by

a 24hr infusion of magnesium or placebo. A CT

head scan is required within 24 hours of randomization.

 

Follow up over 48hrs consists of patient demographic information,

blood pressure measurements (15 minutes, 12hrs, 24hrs and 48hrs post

infusion) and adverse event reporting. Outcome assessment is based

upon clinically relevant end-points (combined death and disability)

at 30 days.

 

Background

 

Acute stroke is the third leading cause of mortality in the western

world, and the largest single cause of disability. No widely

applicable acute treatment has yet been shown to reduce mortality or

disability.

 

Following acute stroke, ischemic tissue may be divided into the

densely ischemic central core, in which neuronal tissue undergoes

infarction rapidly, and a larger, peripheral zone of critically

perfused tissue

known as the ischemic penumbra.

 

Penumbral neurons (and glia) are functionally compromised but

remain viable for a period of several hours

after onset of ischemia.

 

Although the duration of this 'time window' is

unknown, evidence suggests that it may be up to 48 hours in humans.

 

Within the penumbra, a cascade of metabolic and cellular events

triggered by ischaemia ultimately leads to neuronal death. One

important element in this sequence of events is excessive release of

the

excitatory neurotransmitter glutamate,

 

which pathologically overstimulates post-synaptic receptors (notably

the N-methyl d-aspartate or NMDA receptor)

 

to cause neuronal *calcium overload*,

a trigger of cell death.

 

Treatments which interrupt the ischemic cascade may prevent

infarction of penumbral neurons, and have consistently improved

histological and physical outcome in animal models of stroke.

 

These drugs are collectively known as neuroprotective agents, in

distinction to drugs intended to improve or restore perfusion (e.g.

thrombolytics).

 

Why Magnesium?

 

Intravenous magnesium sulphate protects ischemic neurons in vitro

and in

vivo in standard animal experimental stroke models,

including global 4-vessel forebrain ischaemia (Tsuda et al 1991),

 

permanent middle cerebral artery occlusion (Izumi 1991) and direct

NMDA injection (McDonald et al 1990).

 

Neuroprotection may be due to a number of

properties of magnesium: vasodilatation by magnesium sulphate

increases blood flow to the ischemic cortex (Chi et al 1990) whilst

increasing cardiac output;

 

it prevents cerebral vasospasm (Kemp et al 1993); it is

the endogenous non-competitive blocker of NMDA receptors (Nowak et

al 1984, Harrison and Symmonds 1985), a property which may be

responsible for its efficacy as an anticonvulsant

 

(The Eclampsia Trial Collaborative Group 1995);

 

and it *antagonizes* " calcium entry " to cells via multiple

channels (Iseri and French 1984).

 

After intravenous administration in focal cerebral ischaemia models,

both CSF and brain extracellular

fluid *concentrations* of magnesium are raised significantly

 

(Wester PO, personal communication to Andrew P.J. Bradford).

 

Clinical evidence of central nervous system penetration of

pharmacologically active

concentrations of magnesium after systemic administration comes from

use in pre-eclampsia/eclampsia, where intravenous magnesium raises

CSF concentrations significantly (Thurnau et al 1987) and causes

vasodilatation of the cerebral circulation (Belfort et al 1993).

 

 

Magnesium sulfate is superior to phenytoin as prophylaxis in

pre-eclampsia, and to both phenytoin and diazepam as treatment of

eclamptic seizures (Lucas et al 1995; Eclampsia Trial Collaborative

Group 1995).

 

Magnesium has several advantages over other neuroprotective

agents currently in development.

 

It is inexpensive, widely available, and free of the troublesome

side effects of most pharmaceutical agents

which influence glutamate pathways (Muir and Lees 1995a), which

include

psychosis and acute hemodynamic disturbances.

 

In a double-blind crossover study in volunteers, no significant

effects on blood pressure, heart rate or platelet aggregation were

found. Transient flushing and warmth were reported with intravenous

bolus infusion,

and no other side effects were seen.

 

A pilot trial in 60 acute stroke patients (Muir and Lees 1995b)

treated within 12 hours of stroke onset found no cardiovascular

effects,

and no side effects attributable to magnesium.

 

There was a trend towards reduction of the proportion of patients

dead or disabled at 3 months in the magnesium treated group compared

with placebo (30% v 40%) and improved survival (p=0.07).

 

Power calculations for further studies were

based on these data.

 

A further dose ranging study of magnesium sulfate in 25 acute stroke

patients (Muir and Lees 1995c) has established the optimal infusion

regimen to achieve steady state plasma concentrations rapidly.

 

All doses were tolerated with *no* adverse hemodynamic effects.

 

Previous studies of intravenous magnesium sulfate in stroke have

identified no safety concerns. The only side effect of treatment has

been transient flushing during the bolus infusion.

 

Similar doses have been administered in studies in pre-

eclampsia/eclampsia and acute

myocardial infarction without significant adverse effects.

All effects are transient. Serum concentrations of up to 16mmol/l

have been used effectively.

Intravenous magnesium sulphate is neuroprotective in preclinical

models of stroke, and preliminary clinical data indicate that it is

safe,

well-tolerated and possibly beneficial in acute stroke patients.

 

Why do the trial?

 

Intervention after acute stroke has now been proven in man to alter

outcome (NINDS Study 1995) and neuroprotective drugs are now in

phase III clinical development and may be considered for FDA

approval within

the next 2 years.

 

These other agents carry potentially serious side

effects and substantial cost implications for the health-care

industry.

 

Since there is evidence that intravenous magnesium may improve

outcome and is well tolerated, a large scale clinical trial is now

required.

 

Trial Design

 

IMAGES is a randomized, double-blind, placebo-controlled, parallel

group trial of intravenous magnesium sulphate in 2100 patients with

clinically

diagnosed acute stroke.

 

The primary efficacy analysis will be based on the proportion of

patients dead and disabled 30 days after stroke.

 

Power calculations are

based upon the outcome results of the previously conducted study of

intravenous magnesium sulphate in acute stroke, which are consistent

with other major stroke trials.

 

 

While the trial will include patients

treated up to 12 hours after onset, a sub-group analysis of efficacy

in those treated for ischemic stroke within 6 hours of onset is

planned, and the study has been powered to account for this.

 

IMAGES Trial Procedures - At a glance.

 

Assess patient eligibility

 

Obtain consent

 

Complete Form A - attach to chart

 

Fill out IMAGES order sheet

 

Administer trial medication

 

Annotate clinical notes

 

Observe vital signs and serious adverse events

 

Complete Form B - FAX forms A and B

 

Complete Form C - (48hrs) - FAX form C

 

Arrange follow-up CT/MRI head scan within 7 days - send copy film to

ICC

 

 

Mail copy of Forms A & B & C

 

Notify IMAGES (study nurse or principal investigator) and local IRB

of

adverse events

 

FAX adverse events forms

 

Inclusion Criteria

 

Patients eligible for the study must fulfil the criteria below. They

should have a clinically diagnosed stroke. Symptoms, including limb

weakness, must be present for greater than 1 hour following the

onset.

Clinically diagnosed acute stroke with limb weakness*

Symptoms present for at least an hour and treatment initiation

possible within 12 hours of onset

Age 18 or greater

Previously independent in activities of daily living

Exclusion Criteria

 

Coexisting disease which is likely to prevent outcome assessment

Known chronic renal impairment (serum creatinine > 200 mol/l)

Known intracerebral pathology other than ischemic stroke e.g.

intracranial abscess, subarachnoid hemorrhage, brain tumor (previous

stroke is acceptable if patient meets other criteria)

Coma (best motor response unable to localize pain)

Concomitant experimental therapy or ongoing participation in another

clinical trial

Pregnancy

Clear indication or contraindication for magnesium therapy.

 

Notes:

Onset is taken as the time when last known to be well if patients

awake with stroke.

A CT scan is NOT required before trial entry.

Patients with known (i.e. CT proven) primary intracerebral

hemorrhage are not eligible for the study.

*Limb weakness is present if either of the following criteria are

met:

an inability to maintain arm posture for 15 seconds when held at 90

degrees

an inability to maintain leg position for 5 seconds when held at 30

degrees (these are equivalent to limb weakness scores of 1 on the

NIH stroke scale)

 

Common Questions:

 

What do I do if the patient's symptoms are resolving rapidly?

 

If symptoms are present for more than two hours then they are

unlikely to resolve completely within 24hrs and the patient would be

eligible for the study.

 

Transient ischemic episodes with very rapidly resolving

symptoms are best excluded.

What do I do if the exact time of the stroke is not known?

The time of onset of the stroke is the time at which the patient was

known to be well. In a patient who wakes with symptoms, the time of

onset must be considered the time the patient went to sleep, unless

he/she awoke unaffected at some point during the night. Sometimes a

time of onset can be surmised: for example for a patient who is

found fully clothed, the time of onset may be assumed to be around

the time of patient's normal waking time.

 

How do I know if a patient was previously independent?

A patient who is able to walk, climb stairs, transfer and toilet

with an adaptive device (a walking stick or hand rail) or minimal

help will be considered functionally independent.

Consent

 

Consent will be obtained using the attached form. The form will be

kept in the patient's chart and become part of the medical record.

 

Copies of the consent forms will be retained by local PI.

 

Randomization

 

After informed consent is obtained, the treating physician will fill

out

the IMAGES order sheet. Pharmacy will then provide pre-randomized,

properly identified unit doses of the bolus and infusion.

 

Treatment

 

The treatment pack contains magnesium sulfate or placebo (normal

saline) supplied as two unit doses. The first, labelled " BOLUS "

contains normal saline with or without 16mmol magnesium sulphate,

the second, labelled

" MAINTENANCE " contains normal saline with or without 65mmol

magnesium sulfate.

 

How do I administer the trial medication?

 

The trial solutions are administered via an intravenous cannula

using a controlled rate infusion pump. A bolus dose of 16 mmol is

infused over 15 minutes and then a maintenance dose of 65 mmol is

given over 24

hours. Instructions are included within the treatment pack and on

the label of each bag.

 

Begin the INFUSION after the bolus has been completed and keep the

maintenance infusion running for 24hrs:

 

If the infusion is interrupted for any reason, restart at the same

rate

and keep the maintenance dose running until the whole volume has

been

given: DO NOT try and 'make up for lost time'. If there are problems

with the infusion then please document them on Form C.

 

What are the likely side effects of the treatment?

 

Providing the infusion is given as directed, transient flushing is

the

only likely side effect. Hypotension, muscle weakness and reduced

tendon

reflexes are seen with high serum magnesium concentrations. Caution

should be used in patients who are known to have renal failure, as

magnesium is cleared renally.

 

Blood Pressure Measurements

 

Five recordings of blood pressure and heart rate are required

(baseline,

15 minutes, 12, 24 and 48 hours). The non-paretic arm should be used

wherever possible.

 

What do I do if the patient deteriorates during the infusion?

 

Intravenous magnesium is well tested and has been shown to be safe

in

acute stroke in small trials. Spontaneous changes in the condition

of

stroke patients are common within the first 24hrs and should not be

automatically attributed to the trial infusion. In extreme cases the

infusion may be stopped and the patient will remain within the study

and

be followed up as per protocol. In these circumstances an adverse

event

form must be completed detailing the events to allow adequate safety

assessment.

 

How will the trial affect the management of the patients?

 

All routine diagnostic investigations, therapeutic measures for

secondary prevention of stroke (e.g. administration of aspirin,

heparin,

warfarin) or treatment of complications (e.g. antibiotics) should be

carried out as per routine for each center. For the purposes of this

study the use of unproven or unapproved agents intended solely for

the

acute treatment of stroke other than rTPA (e.g. steroids, calcium

antagonists, thrombolytics) should be avoided, since their

administration will invalidate the patient data.

 

CT Head Scanning Requirements

 

A CT scan of brain must be carried out as soon as possible, and in

all

cases within 24 hours of entry into the study.

 

What do I do if the CT is normal or shows hemorrhage?

 

Not all strokes are evident on CT scan. A normal scan does not

exclude

or invalidate a patient from the trial. If a scan shows hemorrhage

during the infusion period, then the infusion should be continued

and

the patient should continue to be followed up as per the protocol.

 

Patient Demographics

 

Form B should be completed as soon as possible and faxed

 

Adverse Events

 

Adverse events occurring within the first 48hrs should be clearly

documented and a serious adverse event form (Form E) FAX'ed .

Serious

adverse events should be regarded as those events that are

potentially

fatal, life-threatening, seriously disabling or causing significant

therapeutic intervention.

 

Patient Follow Up

 

Patients should be followed up for 48hrs. Any significant change in

the

patient's condition should be noted and Form C completed. If there

are

difficulties, the blood pressure measurements in the patient's notes

that most closely correspond to the correct time interval can be

used.

 

Long term follow up

 

Contact by telephone will be undertaken 30 days following the acute

event (this is a validated method).

 

What is the primary end point of the study?

 

Proportion of patients dead or disabled at 30 days.

 

Comparison between groups will be by intention to treat analysis.

Disability will be measured by the Barthel activities of daily

living

index. Patients scoring >=60 will be considered independent and

those

scoring < 60 will be considered disabled. Patients who die will be

allocated a Barthel score of 0. Both the use of telephone interviews

for

scoring and the dichotomous use of the Barthel score around 60/100

have

been validated previously (Korner et al 1994; Grainger et al 1979).

 

What are the secondary end points of the study?

 

Disability outcome by the modified Rankin score, with patients

scoring

0, 1 or 2 being considered independent and those scoring 3 or more

considered dependent; mortality would be grouped with dependence.

Mortality alone.

Death and disability for patients treated within 6 hours of onset of

ischemic stroke.

Death and disability for patients treated within 12 hours of onset

of

hemorrhagic stroke.

Combined death and disability for lacunar versus hemispheric

ischemic

stroke.

A number of other analyses will be undertaken. These will include

analysis to assess any undue or unexpected adverse events. Regular

reports will be submitted to the safety committee.

 

Statistical Analysis

 

For the entire IMAGES study, 712 assessable subjects are required in

the

1-6 hour period in order to determine a difference (two-tailed) in

outcome of 10% with p of 0.05 and power 80% (assuming 40% of

patients

dead or disabled on placebo). It is assumed that approximately 30%

of

patients will fall within this time window, requiring an eventual

total

of approximately 2100 patients. If all patients randomized within 12

hours are included, the trial has power to detect a difference of 6%

between groups.

 

Final recruitment will be terminated after the required number of

assessable subjects has completed the trial protocol or if a highly

significant mortality effect (p<0.001) is identified at a (planned,

six

month) interim analysis.

 

References

 

1. Belfort, M.A., Saade, G.R., and Moise, K.J.J. The effect of

magnesium

sulfate on maternal and fetal blood flow in pregnancy-induced

hypertension. Acta Obst Gynecol Scand 72:526-530, 1993.

 

2. Chi, O.Z., Pollak, P., and Weiss, H.R. Effects of magnesium

sulfate

and nifedipine on regional cerebral blood flow during middle

cerebral

artery ligation in the rat. Archives Internationles de

Pharmacodynamie

et de Therapie 304:196-205, 1990.

 

3. Grainger, C.V., Dewis, L.S., Peters, N.C., Sherwood, C.C., and

Barrett, J.E. Stroke rehabilitation: Analysis of repeated Barthel

index

measures. Arch Phys Med Rehabil 60:14-17, 1979.

 

4. Harrison, N.L. and Simmonds, M.A. Quantitative studies on some

antagonists of N-methyl D-aspartate in slices of rat cerebral

cortex.

British Journal of Pharmacology 84:381-391, 1985.

 

5. Iseri, L.T. and French, J.H. Magnesium: nature's physiologic

calcium

blocker. American Heart Journal (108):188-193, 1984.

 

6. Izumi, Y., Roussel, S., Pinard, E., and Seylaz, J. Reduction of

infarct volume by magnesium after middle cerebral artery occlusion

in

rats. J Cereb Flow Metab 11:1025-1030, 1991.

 

7. Kemp, P.A., Gardiner, S.M., Bennett, T., and Rubin, P.C.

Magnesium

sulphate reverses the carotid vasoconstriction caused by endothelin-

I,

angiotensin II and neuropeptide-Y, but not that caused by

N(G)-nitro-L-arginine methyl ester, in conscious rats. Clinical

Science

85:175-181, 1993.

 

8. Korner, B.N., Wood, D.S., Siemiatycki, J., Shapiro, S., and

Becker,

R. Health-related information postdischarge: telephone versus

face-to-face interviewing. Arch Phys Med Rehabil 75:1287-1296, 1994.

 

9. Lucas, M.J., Leveno, K.J., and Cunningham, F.G. A comparison of

magnesium sulfate with phenytoin for the prevention of eclampsia.

The

New England Journal of Medicine 333:201-205, 1995.

 

10. McCulloch, J. Excitatory amino acid antagonists and their

potential

for the treatment of ischaemic brain damage in man. British Journal

of

Clinical Pharmacology 34:106-114, 1992.

 

11. McDonald, J.W., Silverstein, F.S., and Johnston, M.V. Magnesium

reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in

perinatal

rats. Neuroscience (letter) 109:234-238, 1990.

 

12. Muir, K.W. and Lees, K.R. Clinical experience with excitatory

amino

acid antagonist drugs. Stroke 26:503-513, 1995a.

 

13. Muir, K.W. and Lees, K.R. A randomised, double-blind,

placebo-controlled pilot trial of intravenous magnesium sulfate in

acute

stroke. Stroke 26(7):1183-1188, 1995b.

 

14. Muir, K.W. and Lees, K.R. Dose-ranging study of magnesium

sulphate

after acute stroke. Eur.J.Neurology 2:7, 1995c. (Abstract)

 

15. Nowak, L., Bregestovski, P., and Ascher, P. Magnesium gates

gluatmate-activated channels in mouse central neurones. Nature

307:462-465, 1984.

 

16. The Eclampsia Trial Collaborative Group. Which anticonvulsant

for

women with eclampsia? Evidence from the Collaborative Eclampsia

Trial.

Lancet 345:1455-1463, 1995.

 

17. Thurnau, G.R., Kemp, D.B., and Jarvis, A. Cerebrospinal fluid

levels

of magnesium in patients with preeclampsia after treatment with

intravenous magnesium sulfate: A preliminary report. Am J Obstet

Gynecol

157:1435-1438, 1987.

 

18. Tsuda, T., Kogure, K., Nishioka, K., and Watanabe, T. Mg2+

administered up to twenty-four hours following reperfusion prevents

ischemic damage of the CA1 neurons in the rat hippocampus.

Neuroscience

44:335-341, 1991.

 

 

 

---

-----------

 

 

 

IMAGES Trial Procedures- Summary

 

All conscious patients presenting with acute stroke symptoms,

including

limb weakness lasting longer than one hour.

 

Assess patient eligibility.

 

Please randomize as soon as possible. Neuroprotection may be

maximally

beneficial within a 3-6 hr time window.

 

Please arrange a CT scan as soon as is possible. A scan must be done

within 7 days of the event.

 

Treatment must be given within the 12 hours of the acute event.

 

Obtain consent.

 

Complete Form A.

 

Telephone Clinphone for randomization and treatment number. Have all

the

details ready, the system is automated and must be completed once

the

call has been made.

 

Check center number and center code.

 

Telephone 0115 9535775 (United Kingdom) and +44 115 9535775

(International).

 

When the details have been accurately logged write down the

allocated

treatment number on Form A. The treatment should then be

administered as

soon as possible.

 

Administer trial medication.

 

The trial solutions are diluted into 50-100 mls of normal saline and

administered via an IV cannula using a controlled rate infusion

pump. A

bolus dose of 16 mmol is infused over 15 minutes and then a

maintenance

dose of 65 mmol is given over 24 hours. Instructions are included

within

the treatment pack.

 

Annotate clinical notes.

 

Observe vital signs and serious adverse events.

 

If serious adverse events occur then FAX an Adverse Event Form (Form

D)

immediately.

 

Complete Form B - fax to the ICC within 72hrs of randomization.

 

Complete Form C (after 48hrs).

 

Arrange CT/MRI head scan within 7 days - send copy of film to ICC.

 

Send copy of Forms A & B & C to ICC within 5 days of randomization.

 

Fax serious adverse events forms to the ICC immediately after the

occurrence.

________________

 

JoAnn Guest

mrsjo-

DietaryTi-

www.geocities.com/mrsjoguest/Genes