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Static Treatment for
Status Epilepticus?
William M Coplin, MD, FCCM
Wayne State University School of Medicine
Detroit, MI USA
RAMPART
Robert Welch, MD
John Maynard Keynes
(1883 – 1946)
Keynes Quotations
• I work for a Government I despise for ends
I think criminal.
• The long run is a misleading guide to
current affairs. In the long run we are all
dead.
• You can't push on a string.
• When the facts change, I change my mind.
What do you do, sir?
• I should have drunk more champagne.
FACED WITH THE CHOICE
BETWEEN CHANGING ONE'S MIND
AND PROVING THAT THERE IS NO
NEED TO DO SO, ALMOST
EVERYONE GETS BUSY ON THE
--John Kenneth Galbraith
PROOF.
Intramuscular Midazolam Superior
to Intravenous Lorazepam for
Prehospital Control of
Status Epilepticus
Would Anyone Change Their
Practice to Use Midazolam IM
Instead of Lorazepam IV on
Inpatient Based On This Study’s
Results?
• Not if patient already has IV
• If they don't, then yes
STARTING AN IV ON AN INPATIENT
BEING SEIZED (BY THE DEVIL)
WITH NO VEINS IS NOT ALWAYS
FAST OR EASY; WOULD ONLY USE
IN THE ABSENCE OF IV ACCESS
Agreed…
• That was the point of the study
• Only looked at prehospital care
• There are a few studies of IM midazolam
vs IV lorazepam in Emergency
Departments
– Didn't show any problems
– Small by comparison to 893 patients in
this trial
Whence Came Convincing Data
Supporting Lorazepam as
Benzodiazepine of Choice for SE?
• Trials in the 1970s – 1980s
• Planned before there was midazolam
• Point of this paper is that prehospital IM
midazolam outperformed IV lorazepam
From Practical Point of View
• Lorazepam has perceived short shelf life
when not refrigerated
• For paramedic service this could have overall
cost implication
• Formulation of Lorazepam - thick and really
viscous to draw up
• Some paramedic protocols use rectal
diazepam (mainly for kids)
• Some not fans of that route
Labeling of Lorazepam
• Restated in the paper
• Label is nonsense if ambulance kept
below 30C most of time
• No reason why ambulances can't carry it
in cooler
• Even if temperature in ambulance rises
intermittently, lorazepam will not be
compromised
American Journal of Emergency
Medicine, 17(4), July 1999
Giving Drug IM
in Status Epilepticus
• Isn't a problem
– As it might be in a conscious child
• In kids 0.15mg/kg midazolam
• Old nostrum about benzodiazepines not
being well absorbed IM came from studies
that injected them into paragluteal fat
– Absorption from actual muscle very
good
Absorption of Diazepam
• Wouldn’t recommend using it for anything
unless there was shortage of other
parenteral benzodiazepines
– Such as we are experiencing at the
moment in the US
• Absorption from muscle is good
– As opposed to gluteal fat
– Problem with older studies
• Just use quadriceps or deltoid
Benzodiazepines IM
Some of 20+ Papers
•
Pharmacokinetics of diazepam administered intramuscularly by autoinjector
versus rectal gel in healthy subjects: a phase I, randomized, open-label, singledose, crossover, single-centre study. Lamson MJ, Sitki-Green D, Wannarka GL,
Mesa M, Andrews P, Pellock J. Clin Drug Investig 2011;31(8):585-97.
•
Diazepam autoinjector intramuscular delivery system versus diazepam rectal gel:
A pharmacokinetic comparison. Garnett WR, Barr WH, Edinboro LE, Karnes HT,
Mesa M, Wannarka GL. Epilepsy Res. 2011 Jan;93(1):11-6.
•
Human safety and pharmacokinetic study of intramuscular midazolam
administered by autoinjector. Reichard DW, Atkinson AJ, Hong SP, Burback BL,
Corwin MJ, Johnson JD. J Clin Pharmacol. 2010 Oct;50(10):1128-35.
•
Pharmacokinetics and clinical efficacy of midazolam in children with severe
malaria and convulsions. Muchohi SN, Kokwaro GO, Ogutu BR, Edwards G, Ward
SA, Newton CR. Br J Clin Pharmacol. 2008 Oct;66(4):529-38.
IF WORRIED ABOUT RESPIRATORY
DEPRESSION, FLUMAZENIL MUST
ALWAYS BE IN THE
ARMAMENTARIUM OF ANYONE
USING A BENZODIAZEPINE FOR
ANY REASON
Registration Trials of Flumazenil
• About 3% of these patients without history
of epilepsy had seizure
– Patients getting it for procedural sedation or
suspected overdose
• Only population-based data
• Giving flumazenil to anyone who presents
with seizures is playing with fire
– Not just patients with heterocyclic overdoses
• Much safer to intubate them (IMHO)
I’D rather eliminate use of needles in
back of bouncing ambulance with
actively seizing patient
What About Intranasal Midazolam?
• Via MAST nebulizer or MAD (Mucosal
Atomizing Device) syringe
• Some paramedics use it as an option
• Don't know of any direct comparisons
– Even for serum concentrations
• Use midazolam 5 mg/mL concentration for
IN administration
Then Treat Them Before You Put
Them in Ambulance…
• Some of support for this trial came from group that
wanted to know if effective treatment for status caused
by nerve agent exposure could be given through
protective clothing without removing gas mask
• Nasal midazolam wouldn't be usable in this
circumstance
• No reason to think that nasal route would be
ineffective, but this is large trial showing that IM agent
works
Nice to Know for ED
• Especially when they are being seized and
you cant get an IV
• Will change my practice probably
Assume IV Midazolam Even
Better?
• 10 mg IV midazolam = apnea
• If patient already has IV access, stick to
lorazepam
– Time from actual injection to cessation of
status shorter with lorazepam
• If patient doesn't have access, greater speed
of performing IM injection gives it advantage
If Patient Already Has IV, Use It
• Study dealt with patients in field
– Showed that time to start IV resulted in longer time to
control SE
• Rate of SE termination because of faster
control?
• Can't exclude possibility that midazolam is just
better anticonvulsant
• Direct comparison in refractory SE, where
patients are already intubated (apnea as an
adverse effect) would not be relevant
– Hampered by vehicle for lorazepam (propylene and
polyethylene glycols, and benzyl alcohol) which can
produce profound metabolic acidosis at large doses
required
San Francisco Chronicle (2/16/12)
• According to a study published in the New England
Journal of Medicine, "seizures should be treated by a
single, emergency shot into the thigh much they way
EpiPens are used to treat allergic reactions, rather
than a painstaking procedure that involves an IV while
the patient is convulsing." The findings "are likely to
quickly change how such seizures, which can be lifethreatening if they're not stopped quickly, are treated
by paramedics. But they could have more long-term
repercussions, if doctors start giving the auto-injectors
to epileptic patients, some of whom have several
severe seizures a year, to use at home." The study,
which encompassed 79 hospitals across the US, was
supported in part by the National Institutes of Health
San Francisco Chronicle (2/16/12)
• According to a study published in the New England
Journal of Medicine, "seizures should be treated by a
single, emergency shot into the thigh much they way
EpiPens are used to treat allergic reactions, rather
than a painstaking procedure that involves an IV while
the patient is convulsing." The findings "are likely to
quickly change how such seizures, which can be lifethreatening if they're not stopped quickly, are treated
by paramedics. But they could have more long-term
repercussions, if doctors start giving the auto-injectors
to epileptic patients, some of whom have several
severe seizures a year, to use at home." The study,
which encompassed 79 hospitals across the US, was
supported in part by the National Institutes of Health
San Francisco Chronicle (2/16/12)
• “But they could have
more long-term
repercussions, if
doctors start giving the
auto-injectors to
epileptic patients,
some of whom have
several severe
seizures a year, to use
at home.”
During First Gulf War
• Soldiers were issued autoinjectors of atropine,
2-PAM, and diazepam to use in case of nerve
agent exposure
– Instructions were to use it immediately without
hesitation if people around were suddenly
dropping over with no explanation
• When they would return to base, the atropine
and 2-PAM injectors were almost all returned
• Substantial loss and breakage rate for
diazepam
Diazepam Gel
for Rectal Administration
• Can still give to families
• Can envision few patients
(e.g., with recurrent
status or serial seizures)
for whom autoinjectors of
midazolam might be
appropriate
• Certainly wouldn't want
them to get diverted…
WOULD YOU SUGGEST THIS AS
PART OF THE RAPID RESPONSE
TEAM NURSE PROTOCOL FOR
MANAGEMENT OF THE INPATIENT
IN STATUS EPILEPTICUS WHO HAS
NO IV ACCESS?