TRAINING PROCEDURE FOR INTRANASAL MIDAZOLAM:
Materials required:
1.
2.
3.
4.
Reading material (this protocol) and test
Pencil or pen to take test
Drug delivery devices – 1 per student
Salt water: 1 cup warm water, ¼-1/2 tsp salt, 1/8 tsp baking soda (can also use
saline from a sterile bottle)
5. Paper towels, tissue or cloth towels
6. Student human subjects (may use manikin instead)
DEFINITIONS OF TERMS:
Bioavailability: How much medication that is administered actually ends up in the
blood stream at the source tissue to exert a clinical effect. For example, almost all of a
medication given intravenously is “bioavailable” since it goes strait into the blood stream.
On the other hand, if the medication is given by mouth, most will not be bioavailable in
the blood due to destruction by the acid in the stomach, failure to absorb through the gut
and finally through destruction by the liver in a process called hepatic “first pass
metabolism.” This is why the dose of a medication given intravenously is almost always
far less than that given by mouth.
First-pass metabolism: Almost all molecules absorbed through the gut enter the blood
through the “portal” circulation and are transported to the liver on their way into the main
blood pool of the body. The liver is full of enzymes that breakdown these molecules
(metabolize) and plays an important role in removing toxins from the body. In the case
of medications that are taken by mouth, it is common for most of the medication to be
destroyed by the liver and never make it into the main blood pool of the body. This
destruction by the liver is called “hepatic first pass metabolism”. Drugs that are delivered
by other routes (IV, IM, SQ, nasal) do not enter the portal circulation and are not
subjected to first pass metabolism.
Nose-brain pathway: Since the olfactory mucosa (that area that allows smelling to
occur) is in direct contact with the brain, medication can absorb directly from the
olfactory mucosa into the brain CSF and skip the blood stream/blood brain barrier. This
is called the nose-brain pathway.
Lipophilicity: “Lipid loving” - implies that the molecule will easily absorb and cross a
lipid membrane. Cell membranes are made of lipids. A molecule with high lipophilicity
will easily cross cell membranes (mucous membranes) and enter the blood stream.
INTRANASAL (IN) DRUG DELIVERY
GENERAL PRINCIPLES:
The nasal route is an attractive method of drug delivery due to the rich vascular plexus
that is present within the nasal cavity and the easy accessibility of this vascular bed.
Because of this easily accessed vascular bed, nasal administration of medications is
emerging as a promising method of delivering medications directly to the blood stream.
This method of delivery can eliminate the need for intravenous catheters while still
achieving rapid, effective blood levels of the medication administered.
Administering medications via the nasal mucosal offers several advantages[1]:
1. The rich vascular plexus of the nasal cavity provides a direct route into the blood
stream for medications that easily cross mucous membranes.
2. Due to direct absorption into the blood stream, gastrointestinal destruction and
hepatic first pass metabolism (destruction of drugs by the liver enzymes) are
avoided, allowing more drug to be bioavailable than if it were administered orally.
3. For many medications the rates of absorption and plasma concentrations are
relatively comparable to that obtained by intravenous administration.
4. Ease and convenience: This method of drug administration is essentially painless,
does not require sterile technique, intravenous catheters or other invasive devices
and it is immediately and readily available in all patients.
5. Due to the close proximity of the olfactory nasal mucosa to the central nervous
system, CSF drug concentrations may exceed plasma concentrations, making this
an attractive method of rapidly achieving adequate CSF drug concentrations for
centrally acting medications.
FACTORS THAT AFFECT DRUG BIOAVAILABILITY:
Characteristics of the drug:
 Molecular size, complexity and lipophilicity
 pH of solution and pKa of the drug
 Drug concentration/volume of solution
 Properties of the formulation vehicle (absorption enhancers)
In general, medications that consist of small, simple, lipophilic molecules will
cross membranes most easily. Having a pH near physiologic helps as well.
Finally, if the drug concentration is such that it can be delivered in a reasonable
2
volume to the nose so no runoff into the throat or out the nostril occurs, then more
absorption and higher bioavailability is possible.
In some situations, the medication does not fulfill these features so
pharmaceutical companies re-engineer the medication so it is solubilized in a
enhancer that helps it cross the mucous membrane. Once absorbed, the enhancer
is released and the medication is present in its active form.
Mechanical factors:
 Site of drug deposition
 Method of administration and subsequent particle size and distribution
 Mechanical drug loss anteriorly and posteriorly
The larger the nasal mucosal surface area that is covered, the more medication
that can be absorbed. Ideally, drug doses will be divided in half, and each nostril
received half the dose, which doubles the absorptive surface area. In addition, a
significant difference in drug distribution is observed when various modes of
medication administration are used: nose drops, plastic bottle nebulizer,
atomization pump, pressurized aerosol. Multiple studies show that the atomized
pump is the best nasal delivery system because it gives a constant dose and a very
good mucosal distribution.[2, 3] In addition, research has demonstrated that
clearance of spray is much slower than clearance of drops[4] since much of the
spray deposits on nonciliated areas, whereas nose drop solutions are primarily
distributed on ciliated surfaces. Particle size also affects distribution. With nasal
breathing, nearly all particles with a size of 10-20 µm are deposited on the nasal
mucosa, those less than 2 µm pass through the nasal cavity and deposit in the
lungs.[5, 6] If drugs are introduced as soluble particles they may readily pass into
the nasal lining secretions and then be absorbed into the blood.
Anatomic features of the patient
 Blood flow to the nasal mucosa
 Rate of clearance (ciliary activity)
 Pathologic conditions affecting nasal function
If blood flow to the nasal mucosa is poor, absorption of drug will be poor. This
can occur in situations where previous events have destroyed the nasal mucosa
(trauma, surgery, cocaine induced destruction of the mucosa). Topical
vasoconstrictors such as recent “snorting” of cocaine will also dramatically reduce
absorption. Finally, if the patient has a bloody nose or large volumes of mucous
production, the applied medication is either washed off, or has trouble gaining
contact with the nasal mucosa and cannot be absorbed.
3
INTRANASAL (IN) MIDAZOLAN IN EMS:
Midazolam is a small molecule solubilized in a slightly acidic solution. Plasma
bioavailability ranges from about 55% (nasal drops) to 85% (atomized solution) when
administered onto the nasal mucosa. Nasal midazolam allows effective plasma and CSF
concentrations to be rapidly achieved and offers the added benefit of reducing needle
stick risk to the EMS provider who is treating patients suffering from acute seizures as
well as improved efficacy over rectally delivered medications. The following discussion
reviews these issues in greater detail:
Discussion: Transmucosal Midazolam for Seizures
Status epilepticus is a common neurological emergency, carrying high morbidity and
mortality.[7-9] Because seizure duration greatly impacts outcome, early intervention can
decrease morbidity and mortality. [7, 8, 10, 11] In a recently published prospective study,
Alldredge et al found that prehospital treatment of status epilepticus not only reduced
seizure duration but also reduced the incidence of respiratory complications.[10, 12]
Diazepam (Valium) is the most widely used drug for the emergent management of
seizures in both adults and children.[13] Diazepam must be given intravenously or
rectally since absorption is slow and erratic if given via the intramuscular route.[14-17]
Though intravenous diazepam is fairly effective, it is not as effective as midazolam
(Versed), thiopental, or pentobarbital.[8] In addition, due to the difficulties of
establishing an IV in a seizing patient, administration of medications intravenously may
result in delayed seizure control, especially in children.[18-20] Rectal diazepam offers an
alternate method of delivery,[12, 21, 22] but has a much lower peak concentration, a
slower onset of action, and due to patent protection the commercially available rectal
diazepam product is considerably more expensive than generic intravenous diazepam or
midazolam.[23, 24] In addition, rectal drug administration is less socially acceptable than
other routes.[9] Intramuscular therapy with midazolam is a reasonable alternative and is
as effective as IV diazepam[18] though not quite as effective as IV midazolam.[25]
Transmucosal drug delivery offers an attractive alternate route for the administration of
benzodiazepines, especially midazolam, in seizing patients.[9, 20, 26-31] Because
midazolam becomes lipid soluble at physiological pH, it crosses lipid membranes such as
the nasal mucosa and the blood brain barrier. [32] Transmucosal midazolam delivery
results in a rapid rise in both the plasma and the CSF concentrations [33] with peak
plasma concentrations approximately 5-12 minutes after intranasal administration.[34,
35] This rapid plasma availability of transmucosal midazolam allows it to be
administered intranasally or intraorally by properly trained parents as well as by EMS
medical providers, nurses and physicians, with no need for a needle or an intravenous
line.
4
Multiple studies exist that demonstrate intranasal midazolam is superior to rectal
diazepam and equivalent to IV diazepam for controlled status epilepticus in the
outpatient, pre-hospital and ED setting. Fisgin et al, compared intranasal midazolam to
rectal diazepam in seizing patients and found the nasal route effective 87% of the time
while the rectal route was only effective 60% of the time.[36] Scott and Camfield found
sublingual and buccal midazolam as effective as rectal delivery, but much preferred by
the providers.[9, 37] Holsti compared rectal diazepam to nasal midazolam in the prehospital setting.[38] The rates of pre-hospital seizure control (100% vs 78%), 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 to the rectal diazepam
group. All these authors conclude that intranasal midazolam is more effective than rectal
diazepam as well as more socially acceptable. Two additional studies note that intranasal
midazolam is just as effective as intravenous diazepam for seizure control.[28, 39] Lahat
et al found that nasal midazolam stopped 23 of 26 (88%) seizures while 24 of 26 (92%)
were controlled with IV diazepam (p = NS). The mean time from patient arrival to
seizure cessation was 6.1 minutes with intranasal midazolam and 8.0 minutes with
intravenous diazepam. A similar study was conducted by Mahmoudian, et al.23 These
authors compared the efficacy of intranasal midazolam (0.2 mg/kg) to intravenous
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 via
EMS and at home by families of seizure prone children after appropriate instruction.
All these reports confirm that intranasal midazolam is safe and effective for
treating seizures in the hospital, prehospital and outpatient settings. Compared to the
current “standard” of rectal diazepam, intranasal midazolam is preferred due to its
superior efficacy, ease of use, reduced postictal period and more dignified route of
administration. These findings all suggest that intranasal midazolam should replace rectal
diazepam as the preferred method for treating prolonged seizures in patients without IV
access in place.
In conclusion, because IV lines are difficult to establish in seizing children, and
rectal therapy is less socially acceptable, alternate means of delivering antiepileptic
medications are attractive. The intranasal route and/or buccal route of drug administration
offers an effective alternative delivery method that eliminates the risk of emergency
provider needle stick exposure and may be an attractive alternative in the prehospital
seizing patient.
5
TRAINING DISCUSSION:
Consider the following points prior to actually using the devices:
Midazolam mechanism of action:
 Midazolam is a benzodiazepine class anti-seizure medication. It exerts its antiseizure effect by binding to benzodiazepine receptors in the brain and enhancing
GABA effect. This reduces brain excitability and suppresses seizure activity.
Intravenous (IV) midazolam absorption and the blood brain barrier:
 When midazolam is injected intravenously, we define it as being 100%
bioavailable. No higher peak plasma levels are possible than following an IV
bolus of the drug.
 Midazolam, however, must pass out of the plasma and enter the cerebrospinal
fluid (CSF) in order to exert its effect on the brain and stop seizures. To do this it
must pass through a membrane called the blood brain barrier. This absorption
across the blood brain barrier takes a few minutes, so patients do not stop seizing
instantly following IV midazolam.
Intranasal (IN) midazolam bioavailability and the nose-brain pathway:
 The nasal mucosal membrane is in close contact with the blood stream (via the
nasal mucosal vasculature). It is also directly in contact with the brain through
the olfactory mucosal nose-brain pathway (the area of smell at the top of the nasal
cavity).
 Because the nasal mucosa offers a convenient entry point into both the blood
stream and the CSF for certain molecules, many medications as well as drugs of
abuse are administered through the nasal passage.
 Midazolam is a small molecule that easily crosses membranous surfaces and will
rapidly cross the nasal mucosal membranes both directly into the blood and into
the CSF. Animal and human studies measuring midazolam bioavailability have
found it to be 55% to 85%. Midazolam is more bioavailable if it is atomized than
if it is sprayed or dripped into the nose.
 These factors allow midazolam to be delivered via the nasal route to stop seizures
without the need to establish an IV (a similar reasoning allows benzodiazepines to
be delivered via the rectal route).
Intranasal (IN) midazolam: Drug concentration and volume
 Particle size of delivered medication: Large drops of medication tend to run
down into the throat and are not available for nasal absorption. Spray and
atomized particles distribute more evenly over a larger surface area, making
absorption more effective.
 Volume of delivery: The nasal mucosa will become saturated if too large a
volume of medication is applied to its surface, this results in runoff out the nose or
into the back of the throat, reducing the amount of drug available for absorption
6

Concentration of medication: If the drug that is administered is too dilute, then
sufficient quantities of drug will not be available for absorption. Concentrated
solutions are more effective.
 IMPORTANT: It is imperative to use midazolam 5mg/ml concentration
for nasal drug delivery. The less concentrated form (1mg/ml) requires
higher volumes and is less effective.
Problems with nasal drug delivery:
 Damage to the nasal mucosa: If the nasal mucosa is injured (by trauma) or
destroyed (by chronic cocaine use) then reduced mucosal surface area exists, and
it is unlikely that nasal drug delivery will be effective.
 URI, secretions: Patients with active URI that have large amounts of mucous
secretion, as well as those who are suffering a bloody nose will not absorb the
medications as well because the medication will have difficulty contacting the
nasal mucosa.
 Perfusion: Severe hypotension, severe vasoconstriction, etc will reduce blood
flow to the nasal mucosa and may prevent adequate absorption.
 IMPORTANT: If a patient fails to stop seizing following nasal
midazolam, they may still respond to intravenous midazolam.
Therefor, if the patient fails to stop seizing after nasal midazolam, an
IV should be started, and standard seizure protocol followed.
7
Procedure Practice:
All students should practice calculating doses of IN midazolam as well as practice using
an atomizer to understand how it generates an atomized mist. The device operates via
hydraulic forces, so adequate compression is required to create a fine misting spray.
Calculating midazolam dose:
Intranasal midazolam will require appropriate dosing to be effective yet safe. In the heat
of the moment it may be very difficult. It is probably a good idea to have the following
table (or one using the dosage determined by your medical director) printed up as a 3X5
card that can be carried in the drug kit:
Patient age (yr)
Weight (kg)
IN Midazolam volume in ml*
5mg/ml concentration
midazolam volume dose (mg)
0.3 ml
0.6 mg
0.4 ml
1.2 mg
0.5 ml
2.0 mg
0.7 ml
2.8 mg
0.8 ml
3.2 mg
0.9 ml
3.6 mg
1.0 ml
4.0 mg
1.0 ml
4.4 mg
1.1 ml
4.8 mg
1.2 ml
5.2 mg
1.3 ml
5.6 mg
1.4 ml
6.0 mg
1.4 ml
6.4 mg
1.5 ml
6.8 mg
1.8 ml
8.0 mg
2.0 ml
10.0 mg
Neonate
3
<1
6
1
10
2
14
3
16
4
18
5
20
6
22
7
24
8
26
9
28
10
30
11
32
12
34
Small teenager
40
Adult or full grown 50 or more
teenager
* This volume is based on the calculated dose PLUS 0.1 ml dead space that tends to
remain in the delivery device and rounded off to the next highest 0.1 ml. Slightly higher
doses may be appropriate at the lower range of volume due to measurement difficulties
and possible under dosing which may not stop the seizure.
8
If no card exists, the students should be familiar with how the dose is calculated.
Therefore, practicing dosage calculations is helpful.
Have students calculate patient weights based on a variety of ages:
 Assess weight: children weight in kg = 10 + 2(Age in years)
Now have them calculate the appropriate mg dose, and ml volume of drug they should
administer:
 Calculate appropriate dose of midazolam using the following formula:
o Children: Total kg wt X 0.2 mg = total mg dose of midazolam, (Maximum
of 10 mg)
o Adults over 50 kg: 10 mg (2 ml) of midazolam
 Calculate the appropriate volume:
o Total volume in milliliters of midazolam (5mg/ml concentration) = Total
mg dose divided by 5mg per ml plus the dead space* (0.1 ml)
 *There will be 0.1 ml of solution remaining in the device that
needs to be considered when treated children. This is 0.6 mg of
5mg/ml midazolam
PRACTICE:
GENERAL:
 Have students draw up 2 ml of salt water into a 3 ml luer lock syringe.
 Expel all air from the syringe.
 Connect the atomizer tip to the syringe.
 Briskly compress the syringe plunger to atomize the fluid.
 Vary the pressure applied to the syringe and note that slow compression fails to create
an adequate atomized mist.
 Now practice atomizing 3/10 ml of solution and stopping, then atomizing a different
volume and stopping.
Practice procedure on students or on manikin:
 Students should pair up.
 One student should lie supine
 The second student should draw up a 1.0 ml of solution.
 Expel all air from the syringe.
 Connect the atomizer tip to the syringe.
 Hold the student “patient” head with one hand
 Place atomizer 1.5 cm within one nostril with the other hand.
 Briskly compress syringe to administer 1/2 ml of atomized spray. (This might
irritate the nose slightly so have the towel handy to catch any secretions).
 Remove and repeat in other nostril, so all 1 ml of solution are administered.
 Switch places and let the second student do the same procedure.
9
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