Intravenous magnesium neuroprotective in preclinical models of Stroke patients

[Guest guest]

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. High doses of magnesium, e.g. raising serum magnesium

concentration to 4mmol/l, are known to cause neuromuscular transmission failure

with loss of deep tendon reflexes, progressing to neuromuscular ventilatory

difficulties at higher serum concentrations. All effects are transient. Serum

concentrations of up to 16mmol/l have been survived with appropriate supportive

care.

 

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

mrsjoguest

DietaryTipsForHBP

http://www.geocities.com/mrsjoguest

 

 

 

 

 

 

 

The complete " Whole Body " Health line consists of the " AIM GARDEN TRIO "

Ask About Health Professional Support Series: AIM Barleygreen

 

" Wisdom of the Past, Food of the Future "

 

http://www.geocities.com/mrsjoguest/AIM.html

 

PLEASE READ THIS IMPORTANT DISCLAIMER

We have made every effort to ensure that the information included in these pages

is accurate. However, we make no guarantees nor can we assume any responsibility

for the accuracy, completeness, or usefulness of any information, product, or

process discussed.

 

 

 

 

 

 

 

 

 

Finance Tax Center - File online. File on time.