Intranasal Medications in the
Prehospital Setting
The problem!
 The CDC estimates:

600,000 percutaneous injuries each year
involving contaminated sharps.
 Technological developments can increase
protection.

Not being universally used (cost $, cumbersome,
time-consuming).
…in the field!
 High risk patients

HIV+ patients = 4.1-8.3/100 transports

Marcus et al, Ann Em Med, 1995
 High risk environments

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Altered patients, combative
Scene control issues
Moving ambulance
Risk of exposure…
 Marcus et al, Ann Emerg Med, 1995

Number of exposures in the field:
Blood contacts = 4.9/100 shifts
 Percutaneous = 0.8/100 shifts

 Reed et al, JEM, 1993

Total exposures = 4.4/1000 EMS calls


Needle sticks = 0.24/1000 EMS calls
Level III exposures = 1.3/1000 calls
ALS personnel = 1.1/1000 ALS calls
 BLS personnel = 1.4/1000 BLS calls

OSHA
 Occupational Exposure and Bloodborne
Pathogens Standard

Published in 1991

“…to reduce or eliminate the hazards of occupational
exposure, an employer must implement an exposure
control plan… The plan must describe how an
employer will use a combination of engineering and
work practice controls… Engineering controls are the
primary means…and include the use of safer medical
devices…”
OSHA
 Needle stick Safety and Prevention Act



Continued concern over exposures and lack of
universal technological developments
Signed into Law Nov. 6, 2000
Revised on April 18,2001
“Minimal” requirements for all states
 Applies to all employers with employees at risk
 Greater detail on “engineering controls,” such as safer
medical devices

OSHA
 Needle stick Safety and Prevention Act.

“Non-managerial employees responsible for
direct patient care must have input into employer
decisions about WHICH engineering controls to
adopt” regarding reduction of needle sticks, “not
WHETHER or not to adopt them.”
Exposure Control Plan
 The employer must:

Take into account innovations in medical
procedure and technological developments that
reduce the risk of exposure…

Document consideration and use of appropriate,
commercially-available, and effective safer
devices…

No one device is considered appropriate or
effective for all circumstances
Employee input
 Employers must solicit input




Non-managerial employees
Direct patient care
Identification, evaluation and selection of
effective engineering controls, including safer
medical devices
Employee input must be documented!
Safer Medical Devices
 Needleless devices



Needleless hubs
Jet injection systems
“Needleless” drug administration routes:

Nasal, Buccal, Oral, Rectal, Transdermal, etc
 Shielded needle systems
 Plastic capillary tubing
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:




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
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Its easy and convenient
Almost everyone has a nose
The nose is a very easy access point for medication
delivery
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
 Bioavailability
 First pass metabolism
 Nose brain pathway
 Lipophilicity
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 discussed in this lecture range in
the 55% to 100% bioavailability range - approaching
IV delivery systems.

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 bodies
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 area in nose)
is in direct contact with the brain and CSF.
 Medications absorbed across the olfactory
mucosa directly enter the brain.
 This area is termed the nose brain pathway
and offers a rapid, direct route for drug
delivery to the brain.
Lipophilicity
 “Lipid Loving.”


Cellular membranes are composed on layers of
lipid material.
Drugs that are lipophilic are easily and rapidly
absorbed across the mucous membranes.
Intranasal Medication
Administration: Advantages

Drugs absorbed via the nasal mucosa:



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Are absorbed via the rich vascular plexus of the nose
and directly enter the circulation.
Avoid the stomach and small intestine so are not
destroyed by acid and digestive enzymes, nor delayed
in their absorption to the blood stream.
Avoid the portal circulation, so are not subject to
extensive destruction by the liver.
Can be absorbed directly through the olfactory mucosa
into the CSF - giving rapid brain levels of the drug.
Intranasal Medication
Administration: Advantages
 Compared to oral medications, intranasal
medication delivery results in:



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Faster delivery to the blood stream
Higher blood levels
No destruction by stomach acid and intestinal enzymes
No destruction by hepatic first pass metabolism
Intranasal Medication
Administration: Advantages
 Compared to IV medications, intranasal
medication delivery results in:


Comparable blood levels depending on the drug and dose.
Higher brain levels if well absorbed across the olfactory
mucosa.
Intranasal Medication
Administration: Bioavailability
 Not all drugs can be delivered via the nasal mucosa.
 Factors affecting bioavailability:



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Medication characteristics.
Medication volume and concentration.
Nasal mucosal characteristics.
Delivery system characteristics.

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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:

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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 over 1 ml per nostril are likely too dilute and
may result in runoff out of the nostril.
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 s/a cocaine prevent absorption.
 Bloody nose, nasal congestion, mucous discharge all
prevent mucosal contact of drug.
 Destruction of nasal mucosa from surgery or 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:
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Particle size 10-50 microns adheres best to the
nasal mucosa.
Smaller particles pass on to the lungs, larger
particles form droplets and run-out of the nose.
Intranasal Medication Administration:
Factors Affecting Bioavailability
 Delivery system characteristics (continued):

Atomization results in higher bioavailability than
either spray or drops.

For this reason, nasal pharmaceuticals come with
atomized drug delivery systems.
Mucosal Atomization Device
(MAD)
 MAD - Mucosal
Atomization device:


Device designed to
allow emergency
personnel to delivery
nasal medications as an
atomized spray.
Broad 30-micron spray
ensure excellent
mucosal coverage.
Intranasal Medication Administration:
Factors Affecting Bioavailability
 Points:


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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: What
Medications?
 FDA approved:

A large number of medications ranging from nasal
steroids to antibiotics to opiate anesthetics are FDA
approved.
 Non-FDA approved:

Many other medications are effective via the nasal
mucosa but for a number of financial reasons (as opposed
to medical reasons) the pharmaceutical companies have
not pursued FDA clearance for nasal delivery.
Nasal Drug Delivery in EMS:
What Medications?
 Drugs of interest to EMS systems:

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Intranasal naloxone (Narcan)
Intranasal midazolam (Versed)
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

“Atomization” of medications show much better
absorption via the IN route

Thorsson et al, Br J Clin Pharmacol, 1999
The Denver Experience…
 Denver Health Paramedic System

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Administering 600-800 doses of naloxone
(Narcan®) a year intravenously to patients
Sheathed needles were not used properly
No change in incidence of bloodborne
exposures
“Intranasal Administration of
Naloxone by Paramedics”
 Prospective clinical trial
 Preliminary study February, 2001

Barton et al, Prehosp Emer Care, 2002
 Final study completed August, 2001

Presented at:


The First International Congress of Emergency Medicine, Stresa,
Italy, September 2001
ACEP Scientific Assembly Research
Forum, Chicago, IL, October 2001
Prehospital IN Naloxone
 Study Purpose

To test the efficacy of IN Naloxone in the
prehospital setting:
Number of IN responders?
 Time to patient response?
 How many required repeat doses?


Determine what percentage of IV placements
could potentially be avoided in the field
Prehospital IN Naloxone
 Methods

Clinical indicators for naloxone:

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“Found down” (FD)
“Suspected overdose” (OD)
“Altered mental status” (AMS)
Patients given 2mg IN naloxone at first contact

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1 mg via Mucosal Atomizer Device (MAD) into each nostril
(2mg total of 2mg/2ml solution)
Same dose as given IV by protocol
IN Naloxone by Paramedics
Prehospital IN Naloxone
 Mucosal Atomizer Device (MAD)


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Single-use
Disposable
Fits on standard syringe
Manufactured by Wolfe-Tory Medical, Inc.,
Lake City, UT
 Devices donated for study

Salt
Mucosal Atomizer Device (MAD)
IN Naloxone by Paramedics
Prehospital IN Naloxone
 Methods (cont.)
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Standard protocols followed including airway
management, establish IV, IV meds (naloxone,
D50) if needed
Medics could discontinue protocols if patient
responded appropriately
Times of initial patient contact, IN naloxone, IV
placement, IV naloxone, and patient response
were recorded to nearest minute
Prehospital IN Naloxone
 Results (cont.).

43/52 (83%) = “IN Naloxone Responders.”
Mean time = 3.9 minutes (range 1-11 min.).
 Median time = 3 min.
 Mean time from first contact = 9.9 min.
 Median time from first contact = 8 min.

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9/52 (17%) = “IN Non-responders.”

4 patients noted to have “epistaxis,” “trauma,” or
“septal abnormality.”
Prehospital IN Naloxone
 Results (cont.)

IN Naloxone Responders
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12/43 (29%) got no IV in the field

7/43 (16%) required additional dose of IV naloxone
 “leakage from L nares”
 “aroused slowly”
 “recurrent somulence”
 “2mg IV given due to slow response”
 “lower IN dose - spilled filling syringe”
 “pt responded within 90-120 sec, but still had decr LOC
Prehospital IN Naloxone
 Conclusions
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IN naloxone effective route
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Inexpensive device
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83% response in the field
MAD
May decrease prehospital blood exposures
29% no IV in the field
 Higher risk populations in this setting

Other Naloxone Studies…
 IV vs. SQ Naloxone:

Wanger et al, Acad Emer Med, 1998.
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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.
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 MAD, then begin standard care.
Successful awakening eliminates the need for any IV or further
ALS care.
Awakening is gradual, 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.
Prehospital IN Midazolam
 Why intranasal midazolam for seizures in
the EMS setting?
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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.
IN Midazolam
 Supporting data:
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Nasal midazolam has been extensively
studied for over a decade with hundreds of
studies published regarding its
effectiveness for sedating children.
Very effective for treating acute seizures
and status epilepsy.
IN Midazolam
 Sedation

Henry et al, Pediatr Dent, 1998
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IV vs. IN drop vs. IN atomized midazolam in dogs
Conclusions: Both nasal routes produced higher CSF
concentrations; atomized higher than IN drops
Malinovsky et al, Anaesthesia, 1995

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Oral vs. IN vs. rectal midazolam in kids
Conclusions: Sedation occurred sooner with IN meds (7.7min vs.
12.5min rectal)
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
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: Atomize
into nose with MAD, then begin standard care.
 Efficacy: No quite 100% effective so failures with
nasal may need follow-up with IV therapy.
Other IN Medications
 ALS Drugs

Bleske et al, Am J Emerg Med, 1996
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IN epinephrine and phentolamine in dogs during CPR
Conclusions: There is a dose response effect with IN epi; IN epi
reaches systemic circulation and increases coronary perfusion
pressures
Jelstad et al, Tidsskr Nor Laegeforen, 1995

Case report: Systemic anticholinergic toxicity after IN intake of
atropine
Other IN Medications
 ALS Drugs (cont.)

Scavone et al, Br J Clin Pharmacol, 1989
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Bioavailability of IN lidocaine gel preparation vs. IV lidocaine in
humans
Conclusions: IN absorption was less than 50%
Pontiroli et al, Diabetes Care, 1989


IN vs. IM glucagon in health adults and IDDM
Conclusions: IN glucagon was similar to IM in raising glu
levels; IN was quicker than oral glu
Other IN Medications
 ALS Drugs (cont.)

Dich-Nielsen et al, Acta Anaesth Scand, 1986

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IN NTG on cardiac response to laryngoscopy
Conclusions: IN NTG attenuates pressor response to
laryngoscopy; more effective than IV lidocaine
Hallett et al, Anaesthesia, 2000


Patient-administered IN diamorphine after surgery
Conclusions: IN diamorphine is effective and well-tolerated
without significant side-effects
Conclusions
 Multiple drugs can be given IN


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Rapid
Immediate access
Can be given to almost anyone

Exception = Nasal mucosal abnormalities.
 “Atomization” is the best method



Cheap, easy to use device
Disposable/single use (MAD)
Appropriate drug concentrations
Conclusions
 IN is a true “needleless” system!

Reduce Level III bloodborne exposures



HIV
Hepatitis B, C
Decrease IV placements in the field
Practice!
 MAD function:

Everyone should familiarize themselves with the MAD
before using it in the field.
 Dosing:


IN naloxone: 2 mg (2 ml) – 1 ml up each nostril.
IN midazolam:


Use highly concentrated formulation (5 mg/ml)
Use an age/weight based dosing guide for IN midazolam.
Using the MAD
 1st: Draw up practice solutions:


Saline or water.
Be aware of volume and what dose that would equal.
 2nd: Expel air from syringe.
 3rd: Attach the MAD device via luer lock.
 4th: Briskly compress the syringe plunger.



Brisk brief compression results in controlled atomization.
Gently pushing the plunger will not result in atomization.
With practice you can give an exact volume down to 1/10
of a milliliter.