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Transcript
Intranasal Medications in the
Prehospital Setting
Scenario 1: Broken arm
A 12 year old fell off his bicycle and fractured his
distal arm.
 He is in significant pain.
 EMS protocols call for IN administration of
fentanyl (2 mcg/kg).


10 minutes later the child’s pain is improved but still
substantial.
After a second dose of IN fentanyl he is comfortable.
Scenario 2: Frightened child
A 3-year old boy requires head CT scan (or a
number of other procedures).



He does not have an IV in place and is terrified
of needles.
He will not relax and clings to his parent.
You administer 0.5 mg/kg of IN midazolam and
10 minutes later he is dozing off and is easily
separated from his parent and taken over for his
testing.
Scenario 3: Seizing child
 EMS is enroute with a 3 y.o. girl suffering a grand mal
seizure for at least 15 minutes.
 No IV can be established.
 Rectal diazepam (Valium) is unsuccessful at controlling the
seizure.
 IV attempts in the ED are also unsuccessful.
 However, on patient arrival a dose of nasal midazolam
(Versed, Dormicum) is given and within 3 minutes of drug
delivery the child stops seizing.
Scenario 4: Epistaxis
 A 60 y.o male arrives at the ED with his third episode of
epistaxis in 3 days.
 He was cauterized and packed in another ED the day prior,
but started bleeding 5 hours after the packing was removed.
 You administer 1 ml of oxymetazoline (Afrin) into the
nostril, and insert an oxymetazoline soaked cotton pledget.
 15 minutes later his nasal mucosa is dry.
 You discharge him with instructions to use oxymetazoline
TID for 3 days, and to self treat in the future if possible.
Scenario 5: Heroin Overdose
 EMS responds to an unconscious male. He has slow
respirations, pinpoint pupils, cool dusky skin and obvious
intravenous drug abuse needle track marks on both arms.
 After an IV is established, naloxone (Narcan) is administered
and the patient is successfully resuscitated.
 Unfortunately, the paramedic suffers a contaminated needle
stick while establishing the IV.
 The patient admits to being infected with both HIV and
hepatitis C. He remains alert for 2 hours in the ED with no
further therapy (i.e.- no need for an IV) and is discharged.
Scenario 5: Heroin Overdose
 The paramedic is given his first dose of HIV prophylactic
medications. No treatment for hep C prophylaxis exists.
 The next few months will be difficult: He faces the
substantial side effects that accompany HIV medications and
his personal life is in turmoil due to issues of safe sex with
his wife and the mental anguish of waiting to see if he will
contract HIV or hepatitis C.
 A friend informs him that new evidence suggests that
naloxone is effective at reversing heroin overdose if it is
given intranasally – with no risk of a needle stick.
The problem!
NEEDLESTICKS
 Nasal drug delivery is attractive not because
it is BETTER than injectable therapy……
BUT
 …Because it is SAFER!
..No needle
NO needle stick
risk!
The problem!
NEEDLESTICKS
 The CDC estimates:

600,000 percutaneous injuries each year
involving contaminated sharps in the U.S. A..
 Technological developments can increase
protection.
…in the field! Very high risk
 High risk patients

HIV+ patients = 4.1-8.3/100 transports

Marcus et al, Ann Em Med, 1995
 High risk environments



Altered patients, combative
Scene control issues
Moving ambulance
Intranasal Medication
Administration
 Intranasal Medication administration offers a
truly “Needleless” solution to drug delivery.
 The remainder of this slide show will
surround the topic of intranasal drug delivery
issues.
Intranasal Medication
Administration: Basic Concepts
 This delivery route has several advantages:







Its easy and convenient
Almost everyone has a nose
The nose is a very easy access point for medication
delivery (even easier than the arm, especially in winter)
No special training is required to deliver the medication
No shots are needed
It is painless
It eliminates any risk of a needle stick to you, the medical
provider
Understanding IN delivery:
Definitions
First pass metabolism
Nose brain pathway
Lipophilicity
Bioavailability
First pass metabolism
 Molecules absorbed through the gut, including all
oral medications enter the “portal circulation” and
are transported to the liver.
 Liver enzymes then break down most of these drug
molecules and only a small fraction enter the body’s
circulation as active drug.
 This process is called “First Pass Metabolism.”
 POINT: Nasally delivered medications avoid the
gut so do not suffer first pass metabolism.
Nose brain pathway
 The olfactory mucosa (smelling
Olfactory mucosa, nerve
area in nose) is in direct contact
with the brain and CSF.
 Medications absorbed across the
Brain
olfactory mucosa directly enter
CSF
the CSF.
 This area is termed the nose brain
pathway and offers a rapid, direct
route for drug delivery to the
brain.
Highly vascular nasal mucosa
Lipophilicity
“Lipid Loving”
Non-lipophilic molecules
Lipophilic molecules
 Cellular membranes
are composed of
layers of lipid
material.
Cell Membrane
 Drugs that are
lipophilic are easily
and rapidly absorbed
across the mucous
membranes.
Blood stream
Bioavailability
 How much of the administered medication
actually ends up in the blood stream.

Examples:
IV medications are 100% bioavailable.
 Most oral medications are about 5%-10% bioavailable
due to destruction in the gut and liver.
 Nasal medications vary, but nasal Narcan approaches
100% - the same as when given intravenously.

Bioavailability
Naloxone Serum Concentration
1000
Naloxone conc
 Table demonstrating
naloxone serum
concentrations when
given via IV and IN
routes.
 Note that IV and IN
serum levels are identical
after about 2-3 minutes.
100
Intravenous
Intranasal
10
1
Time
How long does it take you to start an IV in a heroin user?
Intranasal Medication
Administration: Bioavailability
 Not all drugs can be delivered via the nasal mucosa.
 Factors affecting bioavailability:




Medication characteristics.
Medication volume and concentration.
Nasal mucosal characteristics.
Delivery system characteristics.


Mucosal surface area coverage.
Medication particle size.
Intranasal Medication Administration:
Factors Affecting Bioavailability
Medication Characteristics:

Drug characteristics that affect bioavailability
via the nasal mucosa include:





Molecular size.
Lipophilicity.
pH.
Drug concentration.
Properties of the solution the drug is solubilized
within.
Intranasal Medication Administration:
Factors Affecting Bioavailability
Volume and concentration:
Low volume - High concentration.
Too large a volume or too weak a concentration may
lead to failure because the drug cannot be absorbed in
high enough quantity to be effective.
 Volumes over1 ml per nostril are too large and may
result in runoff out of the nostril.

 1/3 to 1/2 ml is ideal in an adult
Intranasal Medication Administration:
Factors Affecting Bioavailability
Nasal mucosal characteristics:


If there is something wrong with the nasal mucosa it
may not absorb medications effectively.
Examples:
Vasoconstrictors such as cocaine prevent absorption.
 Bloody nose, nasal congestion, mucous discharge all
prevent mucosal contact of drug.
 Destruction of nasal mucosa from surgery or past
cocaine abuse – no mucosa to absorb the drug.

Intranasal Medication Administration:
Factors Affecting Bioavailability
Delivery system characteristics:
Nasal mucosal surface area coverage:

Larger surface area delivery = higher
bioavailability.
Particle size:


Particle size 10-50 microns adheres best to the
nasal mucosa.
Smaller particles (nebulized) pass on to the lungs,
larger particles form droplets and run-out of the
nose.
Bioavailability and Particle size
 Compared to drops,
atomized medication
results in:



Larger surface area of
coverage.
Smaller liquid particle
size allowing thin layer
to cover mucosa.
Less run-off out the
nasal cavity.
Intranasal Medication Administration:
Factors Affecting Bioavailability
 Points:



Nasal drug delivery is convenient and easy, but it
may not always be effective.
Nasal drug delivery cannot completely replace
the need for injections.
Being aware of the limitations and using the
correct equipment and drug concentrations will
assist you in predicting times when nasal drug
delivery may not be effective.
Nasal Drug Delivery in EMS:
What Medications?
 Drugs of interest to EMS systems:




Intranasal naloxone (Narcan)
Intranasal midazolam (Versed)
Intranasal fentanyl
Others
Intranasal (IN) Naloxone
 Background

Absorption of IN naloxone almost as fast as IV
in both animal and human models

Hussain et al, Int J Pharm, 1984
 Loimer et al, Int J Addict, 1994
 Loimer et al, J Psychiatr Res, 1992

Atomized spray of medications show much
better absorption via the IN route

Bryant et al, Nucl Med Comm, 1999
 Daley-Yates et al, Br J Clin Pharm 2001
 Henry et al, Ped Dent 1998
“Intranasal Administration of
Naloxone by Paramedics”
 Prospective clinical trial
 Preliminary study February, 2001

Barton et al, Prehosp Emer Care 2002
 Final study completed

Barton et al, J Emerg Med 2005
 Kelly et al, Med J Aust 2005 (a study in Australia)
 Study design:

Required all patients to get an IV and IV naloxone
(standard care) – however nasal naloxone was
administered first and if the patient awoke prior to IV
therapy they could stop.
IN Naloxone by Paramedics
Prehospital IN Naloxone
Results

43/52 (83%) = “IN Naloxone Responders.”
Median time to awaken from drug delivery = 3 min.
 Median time from first contact = 8 min.


9/52 (17%) = “IN Non-responders.”
4 patients noted to have “epistaxis,” “trauma,” or
“septal abnormality.”
 Note – no one waited for them to respond, once IV
started they got IV naloxone so some cases were
given IV naloxone before the nasal drug could
absorb.

Prehospital IN Naloxone
Conclusions

IN naloxone is effective
83% response in the field
 Potentially higher if one waits a few minutes for its
effect prior to giving IV naloxone.


Inexpensive device


Syringe driven atomizer
May decrease prehospital blood exposures

29% no IV in the field (woke up before one could be
started.) Potential for at least 83% with no IV.
Other Naloxone Studies…
 IV vs. SQ Naloxone:

Wanger et al, Acad Emer Med, 1998.



196 patients in Vancouver, BC.
IV naloxone (0.4mg) vs. SQ (0.8mg).
Response time = crew arrival to RR > 10.
 Median response time IV = 9.3 min.
 Median response time SQ = 9.6 min.

Conclusions = No significant difference.
 Delay in SQ response offset by time for IV insertion.
*Median response time IN naloxone = 8.0 min.
Point: IN responses from time of arrival to RR > 10 are
same as those for IV and SQ.
Prehospital IN Naloxone
 Take away lessons for nasal naloxone:
Dose and volume – higher concentration preferred so use
1mg/ml IV solution.
Delivery – immediately on decision to treat inject naloxone into
nose with atomizer, then begin standard care.
Successful awakening eliminates the need for any IV or further
ALS care.
Awakening is gradual-patient doesn’t jump off the bed, but
adequate respiratory efforts occur as fast or faster than IV
naloxone due to no delays with IV start.
Not 100% effective so failures with IN naloxone need to be
followed with IV naloxone.
What if intranasal naloxone
does not work?
 1st - Continue ABC’s to support breathing
and circulation.
 2nd – Administer Naloxone IM or IV.
 3rd - Consider other causes for coma:


AEIOU-TIPPS
Is there anything you can do for these processes?
Protocol: Dosing for IN
naloxone
 Inspect nostrils for mucus, blood or other problems
which might inhibit absorption.
(If these are present, consider other routes and be aware of increased
risk of failure.)
 Draw 2mg of 1mg/ml solution for delivery by
atomizer device.
 Give ½ of volume in each nostril.
 Support ventilations for 3 to 4 minutes, if no
response proceed to IV therapy and consider other
causes for coma.
Midazolam
What is it?

Benzodiazepine related to Valium (diazepam)



Benzodiazepines act on the GABA receptor to
stabilize neural membrane and reduce neuronal
irritation.
Water soluble, pH 3.5 (Valium thick, alkalotic)
Side effects:
Sedation
 Respiratory depression
 Amnesia

Prehospital IN Midazolam
Why intranasal midazolam in the EMS setting?

Seizures




No needles, no need for an IV in a seizing patient.
Rapid delivery – No delays in IV attempts.
Socially acceptable: No need for rectal drug
administration.
As effective as IV therapy, more effective than rectal
therapy, faster onset than either.
Sedation


Agitation/combative patient
IN Midazolam
Supporting data:


Nasal midazolam has been extensively
studied for over a decade with hundreds of
studies published regarding its
effectiveness for sedation children.
Very effective for treating acute seizures
and status epilepsy.
IN Midazolam
Seizures.

Lahat et al, BMJ, 2000.
Prospective study: IN midazolam versus IV
diazepam for prolonged seizures (>10 minutes) in
children.
 Similar efficacy in stopping seizures (app. 90%).
 Time to seizure cessation:

 IV Valium: 8.0 minutes.
 IN Versed: 6.1 minutes.
IN Midazolam
Lahat et al, BMJ, 2000 (cont):

Conclusions:
IV diazepam and IN midazolam have similar efficacy
at controlling prolonged seizures in children.
 IN midazolam controls seizures more rapidly because
there is no delay in establishing an IV.

IN Midazolam
Sheepers et al, Seizure, 2000.
IN midazolam for treatment of severe epilepsy in
adults.
Results: IN midazolam effective in 94% of seizures.
 Conclusion: IN midazolam an effective method for
controlling seizures and is a “more acceptable and
dignified route” than rectal diazepam.

IN Midazolam
Fisgin, J Child Neur, 2002.
IN midazolam versus rectal diazepam for treatment of
pediatric seizure. Prospective trial
 Results:
 IN midazolam effective in 87% of seizures.
 Rectal diazepam effective in 60%

Conclusion:
 IN midazolam is more effective for controlling seizures than
rectal diazepam.
 IN midazolam will be “very useful” in the emergency setting
IN Midazolam
Holsti, Pediatr Emerg Care, 2007.
IN midazolam versus rectal diazepam (PR) for treatment of
pediatric seizure in EMS setting - before an after trial
 Results:
 IN midazolam - 19 minutes less seizure activity on average (11
min IN vs 30 min PR)
 Rectal diazepam

More likely to re-seize (O.R. 8.4)
 More likely to need intubation (O.R. 12.2)
 More likely to require admission to hospital (O.R. 29.3)
 More likely to require admission to ICU (O.R. 53.5)
IN Midazolam
Take away lessons for nasal midazolam:
 Dose and volume: Higher concentration required use 5mg/ml IV solution.
 Dosing calculations are difficult: Use a predefined
age or weight based table to determine dose.
 Deliver immediately on decision to treat: Spray into
nose with atomizer, then begin standard care.
 Efficacy: Not quite 100% effective so failures with
nasal may need follow-up with IV therapy.
Fentanyl
What is it?

Synthetic opiate pain killer
Fentanyl is 50 to 100 times more potent than morphine
 It is 1/2 to 1/3 as long lasting as morphine



Water soluble
Side effects:
Sedation
 Respiratory depression
 Amnesia

Prehospital IN Fentanyl
Why intranasal fentanyl in the EMS setting?

Pain control




No needles, no need for an IV
Rapid delivery – No delays in IV attempts.
As effective as IV morphine in children & adults
Allows adequate pain control without need to establish
an IV in patients that likely do not need IV access
(minor orthopedic trauma and burns)
IN Fentanyl
Borland, Ann Emerg Med, 2007.
IN fentanyl versus IV morphine for treatment of pediatric
orthopedic fractures - Randomized, double blind, placebo
controlled trial
 Results:
 Pain scores identical for IV morphine and IN fentanyl at 5, 10, 20
and 30 minutes
 Less time to delivery of medication via nasal route

Conclusion: IN fentanyl is as effective as IV morphine
for treating pain associated with broken extremities
IN Fentanyl
Rickard, Am J Emerg Med, 2007.
IN fentanyl versus IV morphine for treatment of adult patients
with non-cardiac pain in the prehospital setting Randomized, open label trial
 Results:
 Pain scores identical for IV morphine and IN fentanyl by the time
the hospital was reached
 Less time to delivery of medication via nasal route

Conclusion: IN fentanyl is as effective as IV morphine
for treating pain in adult EMS patients
IN Fentanyl
Caveats:




Borland and Rickard used concentrated fentanyl
(150 to 300 mcg/ml)
U.S. generic fentanyl comes in 50 mcg/ml
concentrations
This lower concentration will likely reduce efficacy
leading to the need to titrate dose
Idea - Sufentanil is more potent than fentanyl and is
very effective in adults for controlling pain
Other IN Medications
 ALS Drugs



Glucagon
?Hydroxycobalamine for cyanide
??others
Conclusions
Multiple drugs can be given IN



Rapid
Immediate access
Can be given to almost anyone

Exception = Nasal mucosal abnormalities.
Delivery method and drugs (generic) are
inexpensive
Conclusions
Intranasal drug delivery is a true “needleless”
system!

Reduce blood borne exposure risks





HIV
Hepatitis B, C
Decrease IV placements in the field
Improve care in situations where an IV cannot be
established.
Equivalent results to IV in many cases, superior to rectal
Educational Web Links
www.intranasal.net