Title: Intranasal%20Medications%20in%20the%20Prehospital%20Setting
1Intranasal Medications in the Prehospital Setting
2Scenario 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 childs pain is improved but
still substantial. - After a second dose of IN fentanyl he is
comfortable.
3Scenario 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.
4Scenario 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.
5Scenario 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.
6Scenario 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.
7Scenario 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.
8The 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!
9The problem! NEEDLESTICKS
- The CDC estimates
- 600,000 percutaneous injuries each year involving
contaminated sharps in the U.S. A.. - Technological developments can increase
protection.
10in 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
11Intranasal 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.
12Intranasal 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
13Understanding IN delivery Definitions
- First pass metabolism
- Nose brain pathway
- Lipophilicity
- Bioavailability
14First 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
bodys 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.
15Nose 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 CSF. - This area is termed the nose brain pathway and
offers a rapid, direct route for drug delivery to
the brain.
Olfactory mucosa, nerve
Brain CSF
Highly vascular nasal mucosa
16Lipophilicity
Non-lipophilic molecules
- Lipid Loving
- Cellular membranes are composed of layers of
lipid material. - Drugs that are lipophilic are easily and rapidly
absorbed across the mucous membranes.
Lipophilic molecules
Cell Membrane
Blood stream
17Bioavailability
- 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.
18Bioavailability
- 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.
How long does it take you to start an IV in a
heroin user?
19Intranasal 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.
20Intranasal 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.
21Intranasal 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
22Intranasal 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.
23Intranasal 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.
24Bioavailability 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.
25Intranasal 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.
26Nasal Drug Delivery in EMS What Medications?
- Drugs of interest to EMS systems
- Intranasal naloxone (Narcan)
- Intranasal midazolam (Versed)
- Intranasal fentanyl
- Others
27Intranasal (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
28Intranasal 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.
29IN Naloxone by Paramedics
30Prehospital 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.
31Prehospital 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.
32Other 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 gt 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 gt
10 are same as those for IV and SQ.
33Prehospital 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 doesnt 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.
34What if intranasal naloxone does not work?
- 1st - Continue ABCs 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?
35Protocol 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.
36Midazolam
- 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
37Prehospital 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
38IN 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.
39IN Midazolam
- Seizures.
- Lahat et al, BMJ, 2000.
- Prospective study IN midazolam versus IV
diazepam for prolonged seizures (gt10 minutes) in
children. - Similar efficacy in stopping seizures (app. 90).
- Time to seizure cessation
- IV Valium 8.0 minutes.
- IN Versed 6.1 minutes.
40IN 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.
41IN 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.
42IN 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
43IN 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)
44IN 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.
45Fentanyl
- 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
46Prehospital 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)
47IN 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
48IN 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
49IN 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
50Other IN Medications
- ALS Drugs
- Glucagon
- ?Hydroxycobalamine for cyanide
- ??others
51Conclusions
- 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
52Conclusions
- 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
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