Therapeutic
Intranasal Drug DeliveryIntranasal midazolam for acute seizure therapy
Introduction
Breakthrough
seizures are all too commonplace in patients with epilepsy.
Some of these seizures will prove to be prolonged.
There are an estimated 150,000 cases of status epilepticus every
year in the US.[1] Caretakers, prehospital and hospital providers are
frequently faced with management of prolonged seizure activity.
As morbidity and mortality are at least partially dependent on
the duration of seizure activity it is crucial that seizures be stopped
as soon as possible.
Transmucosal delivery of benzodiazepines (midazolam or lorazepam)
provides a very effective, safe and inexpensive means to rapidly achieve
seizure control.
Seizures are to a
certain degree self-sustaining.
Because global central nervous system activity is a balance of
excitatory and inhibitory neurotransmission factors that shift the
balance toward excitation can lead to prolonged seizure activity.
Many clinicians have noted through their practice experience that
seizures seem to be self-reinforcing.
A molecular explanation for this phenomenon is beginning to
develop. Mounting evidence
suggests that post-synaptic GABAA receptors are internalized
during status epilepticus thereby reducing neuro-inhibition at the
synapse.[2] The principle first-line agents for the treatment of status
epilepticus are the benzodiazepines, which are GABA agonists.
Therefore the longer a seizure persists the less effective this
class of medicines may be suggesting that the earlier benzodiazepines
are delivered the better.
Transmucosal
delivery of generic benzodiazepines via the nasal mucosa offers an
attractive and cost-effective alternative in the out-of-hospital
setting. Midazolam and lorazepam easily cross the nasal mucosa and the
blood brain barrier, resulting in a rapid rise in both the plasma and
the cerebrospinal fluid concentrations.[3-5]
Wermeling et al.
(2006) Pharmacokinetics and pharmacodynamics of a new intranasal
midazolam formulation (25 mg/ml concentration) in healthy volunteers.[6]
Literature overview and discussion
Three randomized
controlled trials and 1 prehospital observational trial exist, comparing
rectal diazepam to either buccal (oral transmucosal) or intranasal
midazolam.[7-10] Scott et al
conducted a randomized controlled trial comparing buccal midazolam to
rectal diazepam in epileptic students in an extended care school.[7]
A school nurse administered medication to all students who
suffered continuous seizures for more than a 5-minutes. Patients with
persistent seizures for an additional 10 minutes were treated at the
on-call physician’s discretion. Oral transmucosal midazolam was
effective in 75% of cases (30 of 40 seizures), whereas rectal diazepam
was effective in 59% (23/39) ( P = non significant). There were no
adverse cardiorespiratory effects in either group. Although these
differences did not achieve statistical significance, the trend toward a
better outcome along with the more socially acceptable delivery of oral
transmucosal medication led the school to change its preferred treatment
to the oral transmucosal route.
Camfield et al
found
similar efficacy in their randomized trail comparing these 2 routes and
drew identical conclusions—oral transmucosal midazolam was preferred
over rectal diazepam because of ease of use and social acceptability.[8]
The third randomized controlled trial, conducted by Fisgin et al,
compared intranasal (rather than buccal) transmucosal midazolam to
rectal diazepam.[9] In this study, midazolam aborted 20 (87%) of 23
seizures and rectal diazepam 13 (60%) of 22 seizures (P b .05). These
results were statistically significant in favor of the intranasal 130
route when compared with the rectal route. Again, as in previous
studies, no clinically important adverse events were identified in the 2
groups.
The final study,
by Holsti et al, was conducted in a prehospital ambulance setting.[10]
In this study, the entire emergency medical system converted from rectal
diazepam to intranasal midazolam for treatment of pediatric seizures.
The authors compared effectiveness and complication data before and
after the change. The rates of prehospital seizure control (100% vs
78%), need for need for emergent intubation (0% vs 33%), and need for
hospital admission (40% vs 89%) were all substantially less in the
intranasal midazolam group compared with the rectal diazepam group. The
mean seizure duration was 11 minutes for those treated with nasal
midazolam compared to 30 minutes for rectal diazepam.
Children given the rectal medication were significantly more
likely to have another seizure in the ED (odds ratio [OR] 8.4), need ED
intubation (OR 12.2), need hospital admission (OR 29.3) and need ICU
admission (OR 53.5).
All these authors
conclude that trans-mucosal midazolam is more convenient, easier to use,
just as safe, and is more socially acceptable than rectal diazepam.
Furthermore, when given via the intranasal route, midazolam is more
effective than rectal diazepam.
The above evidence
clearly suggests that intranasal midazolam is superior to rectal
midazolam for seizure therapy in children. However, IV benzodiazepines
are first-line therapy in most hospitals—how does intranasal midazolam
compare to IV benzodiazepines? Two randomized controlled trials
comparing intranasal midazolam to IV diazepam answer this question.[11,
12] Lahat et al compared intranasal midazolam to IV diazepam in children
seizing 10 minutes or longer.[11] Patients were randomized to receive
diazepam, 0.3mg/kg IV, or midazolam 0.2 mg/kg intranasally. Nasal
midazolam stopped 23 (88%) of 26,whereas 24 (92%) of 26 were controlled
with IV diazepam (P = non significant). The mean time from patient
arrival to seizure cessation was 6.1 minutes with midazolam and 8.0
minutes with diazepam. The authors conclude that intranasal midazolam
was as safe and effective as IV diazepam, but the overall time to
cessation of seizures after arrival at the hospital was faster with
intranasal midazolam because of the time required to establish an IV
line in the diazepam group. A similar study was conducted by Mahmoudian
and Zadeh.[12] These authors compared the efficacy of intranasal
midazolam (0.2 mg/kg) to IV diazepam (0.2 mg/kg) in 70 patients (ages 2
to 15 years) presenting to the emergency department with seizure
activity. Both methods were equally effective, and no adverse effects
occurred in either group. These authors conclude that nasal midazolam
should be used not only in medical centers but also in general
practitioners’ offices as well as at home by families of seizure-prone
children after appropriate instruction.
Perhaps the
greatest benefit of intranasal midazolam will be for the treatment of
seizures in the prehospital, home or extended care setting. Wilson et al sent intranasal midazolam home with families of
children suffering epilepsy and found that 33 of 40 (83%) who used it
found it effective and 20/24 (83%) preferred using transmucosal
midazolam to rectal diazepam.[13] Harbord reported experience using
intranasal midazolam for home treatment of 54 seizures in 22
children.[14] These authors found it to be 89% effective, with no
evidence of respiratory compromise. Ninety percent of families found no
difficulty with nasal medication administration. Of the 15 parents with
previous rectal diazepam experience, 13 thought intranasal delivery was
easier and 14 preferred it to the rectal route. Jeannet et al, used
intranasal midazolam both on the medical wards and as home therapy.[15]
Their experience with 26 children suffering 125 seizures note a 98%
effectiveness in under 10 minutes with no serious adverse effects.
When compared to rectal diazepam they report that the intranasal
route was both easier to use and that postictal recovery was faster.
Scheepers et al report their experience with intranasal medication
delivery in an extended care facility caring for adolescents and adults
with severe epileptic disorders.[16] Of 84 uses, they found this route
to be effective in 79 (94%). In the 5 instances when it was not
effective, 3 of the 5 doses were delivered intra-orally rather than
intranasally.
Intranasal
lorazepam, another anti-seizure medication, also appears effective and
safe for treating status epilepsy based on a single trial. A large study conducted in rural Africa compared intranasal
lorazepam to intramuscular paraldehyde (a common medication used in the
third world to seizure therapy) in 160 patients, most of whom were
seizing for an extended time period (mean seizure duration was over 2
hours).[17] Despite these prolonged seizures, intranasal lorazepam
managed to stop three quarters of the seizures in a few minutes, while
intramuscular medication only worked 61% of the time. There were no
respiratory side effects seen with the lorazepam.
This data is
fairly compelling. Multiple studies from different authors throughout
the world confirm that intranasal midazolam (and in one study lorazepam)
is a safe and very effective means to achieve seizure control at home,
in the ambulance and in the hospital.
Its rapid onset of action, social acceptability, ease of use and
efficacy suggest that this therapy should be adopted in appropriate
situations (prolonged seizures) where IV access is not immediately
available.
Personal insights from experienced clinicians
Tom Macfarlane, MD. Emergency Physician, Salt Lake City, Utah:
I have extensive experience in using intranasal midazolam in the hospital and home settings. As an emergency physician I frequently care for patients who are experiencing seizures. It is often difficult to establish intravenous access in these seizing patients and therefore transmucosal drug delivery is a great option. I also have a 4 year-old son who experiences frequent prolonged seizures. My family and I have safely administered over 60 transmucosal doses of midazolam over the course of 3 years. This has allowed us to avoid many trips to the Emergency Department and provides us with a degree of increased freedom. I am confident that my son would not be functioning at the level he is today without intranasal midazolam.
Treatment protocol:
Intranasal midazolam for acute seizures
Indications: For treatment of persistent seizure activity
Procedure:
- Assess ABC’s – Airway, Breathing, Circulation
- For pulseless patients, proceed to ACLS guidelines
- Apply 100% oxygen NRB mask to seizing patient
- Use age based table to determine proper volume of midazolam for atomization (see table below)
- To calculate it manually, use the below
formula
-
Assess
weight: children weight in kg = 10 + 2(Age in years)
-
Calculate appropriate dose of midazolam using the following
formula:
-
Children: Total kg wt X 0.2 mg = total mg dose of midazolam,
maximum of 10 mg
-
Adults over 50 kg: 10 mg (2 ml) of midazolam
- Total volume in milliliters of midazolam (5mg/ml concentration) = (Total mg dose divided by 5mg/ml) + 0.12 ml for dead space of device.
-
Children: Total kg wt X 0.2 mg = total mg dose of midazolam,
maximum of 10 mg
-
Assess
weight: children weight in kg = 10 + 2(Age in years)
- Load syringe with appropriate milliliter volume of midazolam (use only 5mg/ml concentration) and attach MAD nasal atomizer
- Place atomizer within the nostril
- Briskly compress syringe to administer 1/2 of the volume as atomized spray.
- Remove and repeat in other nostril, so all the medication is administered
- Continue ventilating patient as needed
- If seizures persist 5 minutes after treating, consider repeating ½ dose of midazolam either intranasally, intramuscularly or intravenously. Secure airway if necessary.
Midazolam Dosing chart
|
Patient age
(years) |
Weight
(kg) |
IN Midazolam volume in ml*
5mg/ml concentration Volume Dose (mg) |
|
Neonate |
3
kg |
0.3 ml
0.6 mg |
|
<1 yr |
6
kg |
0.4 ml
1.2 mg |
|
1 yr |
10 kg |
0.5ml
2.0 mg |
|
2 yr |
14 kg |
0.7 ml
2.8 mg |
|
3 yr |
16 kg |
0.8 ml
3.2 mg |
|
4 yr |
18 kg |
0.9 ml
3.6 mg |
|
5 yr |
20 kg |
1.0 ml
4.0 mg |
|
6 yr |
22 kg |
1.0 ml
4.4 mg |
|
7 yr |
24 kg |
1.1 ml
4.8 mg |
|
8 yr |
26 kg |
1.2 ml
5.2 mg |
|
9 yr |
28 kg |
1.3 ml
5.6 mg |
|
10 yr |
30 kg |
1.4 ml
6.0 mg |
|
11 yr |
32 kg |
1.4 ml
6.4 mg |
|
12 yr |
34 kg |
1.5 ml
6.8 mg |
|
Small teenager |
40 kg |
1.8 ml
8.0 mg |
|
Adult or full-grown teenager |
> 50 kg |
2.0 ml
10.0 mg |
* This volume is based on the calculated dose PLUS 0.10 ml dead space in the device (the amount of medication that will remain within the syringe and atomizer tip and therefore will not be delivered to the child). The total volume is then rounded off to the next highest 0.1 ml. Slightly higher doses may be appropriate at the lower range of volume (in smaller children) due to measurement difficulties and possible under dosing which may not stop the seizure.
In some children a higher dose (0.3 mg/kg) may be more appropriate
Teaching materials
Video of a family successfully treating their seizing child with intranasal midazolam in a city park
-
Delivery of the medication during the acute seizure (click here)
-
Resolution of the seizure approximately 2-3 minutes later (click here)
How to deliver intranasal midazolam at home (click here for photos and directions)
Download a basic photographic display of how to draw up and administer intranasal midazolam for seizures or sedation (click here for MS word document 0.53 MB)
EMS seizure therapy protocols (Click here)
Peer Reviewed full articles
Lahat, IN midazolam for seizures, BMJ 2000 (click here) - PDF 0.25 MB
Krykou, IN midazolam for community seizure therapy, Epilepsy Australia 2006 (click here) - PDF 0.44 MB
Segal, An alternate route of drug administration in acute convulsions, IMAJ 2000 (click here) - PDF 0.09 MB
Bibliography (click here for abstracts)
1.
DeLorenzo, R.J.,
et al., Epidemiology of status
epilepticus. J Clin Neurophysiol, 1995.
12(4): p. 316-25.
2.
Goodkin, H.P.,
J.L. Yeh, and J. Kapur, Status
epilepticus increases the intracellular accumulation of GABAA receptors.
J Neurosci, 2005. 25(23): p.
5511-20.
3.
Wermeling, D.P.,
et al., Bioavailability and
pharmacokinetics of lorazepam after intranasal, intravenous, and
intramuscular administration. J Clin Pharmacol, 2001.
41(11): p. 1225-31.
4.
Knoester, P.D., et
al., Pharmacokinetics and
pharmacodynamics of midazolam administered as a concentrated intranasal
spray. A study in healthy volunteers. Br J Clin Pharmacol, 2002.
53(5): p. 501-7.
5.
Malinovsky, J.M.,
et al., Plasma concentrations of
midazolam after i.v., nasal or rectal administration in children. Br
J Anaesth, 1993. 70(6): p.
617-20.
6.
Wermeling, et al.,
Pharmacokinetics and
pharmacodynamics of a new intranasal midazolam formulation in healthy
volunteers. Anesth Analg, 2006.
103(2): p. 344-9, table of
contents.
7.
Scott, R.C., F.M.
Besag, and B.G. Neville, Buccal
midazolam and rectal diazepam for treatment of prolonged seizures in
childhood and adolescence: a randomised trial. Lancet, 1999.
353(9153): p. 623-6.
8.
Camfield, P.R.,
Buccal midazolam and rectal
diazepam for treatment of prolonged seizures in childhood and
adolescence: a randomised trial. J Pediatr, 1999.
135(3): p. 398-9.
9.
Fisgin, T., et
al., Effects of intranasal
midazolam and rectal diazepam on acute convulsions in children:
prospective randomized study. J Child Neurol, 2002.
17(2): p. 123-6.
10.
Holsti, M., et
al., Prehospital intranasal
midazolam for the treatment of pediatric seizures. Pediatr Emerg
Care, 2007. 23(3): p. 148-53.
11.
Lahat, E., et al.,
Comparison of intranasal midazolam
with intravenous diazepam for treating febrile seizures in children:
prospective randomised study. Bmj, 2000.
321(7253): p. 83-6.
12.
Mahmoudian, T. and
M.M. Zadeh, Comparison of
intranasal midazolam with intravenous diazepam for treating acute
seizures in children. Epilepsy Behav, 2004.
5(2): p. 253-5.
13.
Wilson, M.T., S.
Macleod, and M.E. O'Regan,
Nasal/buccal midazolam use in the community. Arch Dis Child, 2004.
89(1): p. 50-1.
14.
Harbord, M.G., et
al., Use of intranasal midazolam
to treat acute seizures in paediatric community settings. J Paediatr
Child Health, 2004. 40(9-10):
p. 556-8.
15.
Jeannet, P.Y., et
al., Home and hospital treatment
of acute seizures in children with nasal midazolam. Eur J Paediatr
Neurol, 1999. 3(2): p. 73-7.
16.
Scheepers, M., et
al., Is intranasal midazolam an
effective rescue medication in adolescents and adults with severe
epilepsy? Seizure, 2000. 9(6):
p. 417-22.