A Milestone Change in Practice

     Emergency units respond to a report of an unconscious child in a school, where you arrive to find a seven-year-old boy seizing in a restroom. Teachers tell you that he was excused to go to the bathroom, and when he didn't return, a staff member went to check and found him seizing. That was over 10 minutes ago; he hasn't stopped seizing the entire time. The child is cyanotic and in full tonic-clonic activity. After accessing his medical records, school staff deny any previous medical conditions. The nearest medical center is 20 minutes away. Your partner is managing the airway and ventilations while you attempt vascular access and pharmacotherapy. You quickly administer glucagon 1 mg intramuscular and attempt to establish an IV. After two attempts on the flailing child with no veins, you give up. He is still cyanotic and into his 20th minute of seizure activity. You look through your kit and find the IO setup open and contaminated. Now what?

Why Intranasal?
     All emergency care providers, particularly those working in the prehospital environment, are faced with conditions in which their patient urgently needs a medication administered. ALS providers are particularly familiar with intravenous, intramuscular and subcutaneous methods. This article will discuss the recent literature and improvements in delivery systems that result in the potential for widespread utilization of intranasal (IN) drug administration.

     Intranasal drug delivery is supported by recent research into new forms of drug delivery and is emerging as a promising method of delivering medications directly to the bloodstream through absorption across the nasal mucous membranes. This method of delivery can eliminate the need for intravenous catheters or intramuscular needles, thereby reducing needlestick risk while simultaneously delivering effective drug levels. The potential for widespread application of intranasal drug delivery may significantly enhance emergency patient care and increase the pool of emergency care providers who can provide safe and timely medication administration.

A Safer Option
     There is a significant risk associated in EMS with using needles to administer medication. There have been enhancements in the design of safety systems for emergency care, such as needleless catheters and intravenous systems, but there remains a significant risk in the uncontrolled environment.

     A landmark study in the September 2006 Annals of Epidemiology estimated that 21.6% of paramedics reported a blood exposure in the previous year. The rates represented more than 49,000 total exposures and more than 10,000 needlesticks per year among paramedics in the United States.¹ Previous information estimated the annual number of needlestick and other percutaneous injuries among all healthcare workers at 600,000-800,000, with approximately 16,000 of those likely to be contaminated with the human immunodeficiency virus (HIV).2 The rate of occupational transmission from an HIV-positive source is believed to be 0.3% for a percutaneous exposure and 0.09% for a mucous membrane exposure. The rate from a hepatitis B-positive source to a non-immunized host is between 6% and 24%, while the rate for exposure to hepatitis C is 1%-10%.3 This point in itself cannot be overemphasized; a scientific peer-reviewed study is estimating 10,000 needlestick injuries each year to paramedics, and rates of transmission of hepatitis B and C up to 25%. This significant risk is not to be overlooked or ignored and warrants looking into options to decrease it.

     One of the distinct advantages of intranasal administration is lack of contaminated sharps. While the intramuscular and subcutaneous routes are feasible for many emergency medications, once they pierce the skin they are contaminated and pose a threat. As EMS agencies enhance their safety procedures for workers and patients, there is a dual role of intranasal drug administration related to reducing provider risk and improving patient care. The Needlestick Safety and Prevention Act (2001) requires that "(e)ngineering and work practice controls shall be used to eliminate or minimize employee exposure." Engineering controls are defined as, "controls (e.g., sharps disposal container; self-sheathing needles; safer medical devices, such as sharps with engineered sharps injury protections; and needleless systems) that isolate or remove a hazard from the workplace."

Advantages of Nasal Adminstration
     Nasal administration of medications for systemic effect offers several advantages. The rich vascular plexus of the nasal cavity provides a direct route into the bloodstream for medications that easily cross mucous membranes. Due to direct absorption into the bloodstream, rate and extent of absorption and plasma concentration versus time profiles are relatively comparable to those obtained by intravenous administration.^4-6 This method of drug administration is essentially painless, does not require sterile technique, intravenous catheters or other invasive devices, and is immediately and readily available to most patients. Due to the close proximity of 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 (i.e., benzodiazepines for seizures and possibly for sedation). ^4,7,8

Methods of Adminstration
     There are a few different methods and devices for IN administration. This article will focus on the MAD-Mucosal Atomization Device (Figure 1). IN drug delivery using this device is a simple skill to learn and rapidly master, and may provide an opportunity for BLS providers to administer emergency medications.

     If drugs are introduced as soluble particles, they may readily pass into the nasal lining secretions and then be absorbed into the blood.^4,5,9 Medications administered by nasal spray are present for longer time periods than those administered as drops.^4,10,11 In addition, plasma levels show higher drug levels when the medication is sprayed, as opposed to being dripped in.¹¹ Several studies have noted superior effect of atomization over drops and sprays.^10,11 While IN is a promising approach, not all EMS medications can be administered intranasally, and only a few have been studied to date. There are numerous factors to consider regarding which medications are candidates for IN administration, including molecular size, complexity and chemical properties, and drug concentration/volume of solution.

Prehospital Options

Naloxone
     Nasal absorption of naloxone in rats was first studied for publication in 1984 and was proved to be as effective as intravenous naloxone in opiate addicts in 1994.¹² Naloxone is 100% bioavailable through the nasal mucosa, with an onset of action that is indistinguishable from IV naloxone. In a study of IN naloxone use in 95 patients, 52 of the patients responded to naloxone by either IN or IV and 43 of those (83%) responded to IN naloxone alone. Seven patients (16%) in this group required further doses of IV naloxone. The conclusion was that IN naloxone is an alternative method for drug administration in high-risk patients in the prehospital setting with good overall effectiveness.¹³ Washington EMS evaluated the delivery and effect of naloxone for opioid overdose in a tiered-response EMS system to ascertain how much time could be saved if the first-arriving EMTs could have administered intranasal naloxone. In their system, average EMT arrival time was 5.9 minutes; subsequent paramedic arrival was on average 5 to 10 minutes later. The study concluded that there is potential for significantly earlier delivery of naloxone to patients in opioid overdose if EMTs could deliver intranasal naloxone, and that a pilot study training and authorizing EMTs to administer intranasal naloxone in suspected opioid overdose is warranted.¹⁴ Naloxone administration has been studied beyond EMS providers. Researchers in Australia proposed that outreach workers could safely and effectively administer IN naloxone.¹⁵ In New Mexico, laypersons, friends and relatives of IV heroin users are given IN naloxone packages for home therapy. Police and highway patrol have carried IN naloxone to treat overdoses for about five years. (Naloxone is indicated in patients with respiratory depression or altered mental status secondary to opioid overdose.) In the prehospital arena, these patients are typically intravenous drug abusers and prehospital providers may experience difficulty accessing a vein. IN naloxone is a feasible and perhaps favorable mode of administration in this population.

Benzodiazepines
     Intranasal benzodiazepines can be useful for termination of seizures and prehospital sedation. Seizing patients, especially children, are notoriously difficult to secure intravenous access, and the risk of needlestick to the provider increases. Due to these difficulties, alternative methods of administering antiepileptics are necessary. There is also evidence that speed is a necessity. Patients found in status epilepticus whose seizures are terminated prior to arrival at the emergency department have an ICU admission rate of 32% compared with 73% in patients whose seizures persisted on arrival at the ED. In addition, patients in status who are given benzodiazepines in the field by paramedics have a mortality rate between 4.5% and 7.7%, compared with 15.7% for patients given benzodiazepines only after arrival at the ED.¹⁶ The most studied intranasal benzodiazepine is midazolam (Versed). IN midazolam results in bioavailability of 50%-83% when compared to the IV route.¹⁷ With IN, cerebrospinal fluid levels are higher than plasma levels. Nasal midazolam has a slightly slower onset of action and peak effect compared to IV midazolam, but twice as fast an onset and one to three times higher peak plasma levels than rectal and oral midazolam.

     Analysis of a systematic review of the literature (four randomized controlled trials and one observational study that compared midazolam given by IM or IN routes with intravenous diazepam in the emergency setting, either in the ED or in the field) demonstrated that non-intravenous midazolam and IV diazepam have similar efficacy at terminating seizures, but IM/IN midazolam is consistently quicker at terminating seizures, with a fixed weighted mean difference of about three minutes.¹⁶ Research specifically addressing this problem demonstrates seizure control in less than two minutes in 80% of seizing pediatric patients given intranasal midazolam. Intranasal midazolam has also been used successfully by family members of children with seizures.¹⁸ It should be noted that diazepam is mixed in oil and is not formulated for intranasal use. Midazolam is water-soluble and mixed in a way appropriate for IN use.

     A discussion of intranasal benzodiazepines is not complete without discussing the possibility of intranasal flumazenil in treating benzodiazepine overdose. One study indicated that plasma levels attained after intranasal administration were similar to those reported after intravenous administration, and may be sufficient to antagonize the side effects of benzodiazepines.¹⁹ Again, this route of administration may be useful when the intravenous route is not readily available.

Opiates
     Intranasal opiates can also be effectively administered via the nasal mucosa for pain relief and sedation. Studies have shown fentanyl to be as effective as morphine in treating severe, acute pain in a prehospital setting during the first 30 minutes in spontaneous breathing patients, and that intranasal fentanyl is as effective as intravenous morphine in children aged 7-15 years who present to an ED with an acute fracture.²⁰ As recent literature indicates that prehospital providers are not adequately assessing and treating pain as the "fifth vital sign," intranasal opiates may be a simple way to address this deficiency.²¹ Intranasal opiates may also offer faster onset of action, requiring less total dosing and decreasing the possibility of overdose and adverse effects.

Anti-hypoglycemics
     Current treatment for symptomatic hypoglycemia (altered mental status) is to have a family member administer IM glucagon, or for a paramedic or ED personnel to administer IV dextrose. Neither method is optimal. The family member may not administer the IM drug properly, and the IV requires an EMS ALS response or an ED visit, or sometimes both. Intranasal glucagon offers an alternative by generating a rapid rise in blood glucose-not as fast as intramuscular glucagon, but faster than oral glucose.²² There is a debate in EMS circles as to whether patients who were symptomatically hypoglycemic but are asymptomatic after treatment need to be transported to an ED. Most authorities seem to conclude that as long as the patient is fully conscious and can voluntarily intake carbohydrates, there is no need for EMS transport.^23-26 This is barring an underlying cause, such as long-acting insulin overdose or oral hypoglycemic medication misuse. Medical directors, state and responding agencies may want to evaluate use of glucose meters, fingerstick samples and IN glucagon as a Basic and Intermediate EMT skill.

Cardiac Arrest Medications
     A common problem encountered during cardiac resuscitation is the lack of timely vascular access to administer ACLS medications. The endotracheal tube is one alternate route and has proven at least moderately effective. Intraosseous access in adults is only recently developing as a second line of access if intravenous is not accessible. In situations when an endotracheal tube is either not present or not yet inserted, or vascular access has not been attainable, the nasal mucosa offers yet another source for ACLS medication administration. Atropine, epinephrine and vasopressin are all capable of being administered intranasally. While epinephrine given via the nasal route is complicated by the fact that it causes vasoconstriction and therefore reduces its own absorption, this problem was addressed by one group of investigators by topical pretreatment with the vasodilator phentolamine. Using low doses of phentolamine and high doses of epinephrine, adequate circulating epinephrine levels were achieved, leading to improved coronary perfusion pressure during CPR, and improved resuscitation in an animal model.²⁷ Intranasal atropine has been used in organophosphate poisoning, but no attempt in cardiac arrest has been found in the literature.²⁸ Patients have successfully used intranasal desmopressin (DDAVP) for years. Its chemical cousin vasopressin is now a component of cardiac arrest treatment, especially since there is a lack of evidence to show that epinephrine does anything in cardiac arrest.

     While much further research is needed, it is feasible to consider a BLS unit arriving on scene, defibrillating and performing CPR as indicated, but also administering intranasal epinephrine, atropine or vasopressin prior to ALS's arrival.

Anti-emetics
     Meclizine (Antivert) given intranasally is 50%-80% bioavailable and peaks in 8 to 12 minutes-much faster and higher than the oral form of meclizine, and is much better tolerated, considering the drug is for nausea and vomiting.²⁹

Cardiovascular Medications
     The feasibility of intranasal administration of cardiovascular drugs has been investigated in multiple studies. Intranasal propranolol is as rapid and bioavailable as IV propranolol. Diltiazem has successfully been administered intranasally. Intranasal nitroglycerin spray, nifedipine, nicardipine, verapamil and hydralazine are highly absorbed via the nasal mucosa and have been studied.³⁰

Conclusion
     Intranasal administration of some common prehospital medications offers definite advantages, both in safety to the provider and absorption by the patient, although extensive research is still needed on the viability of this system. It is my contention that EMT-Bs and EMT-Is may successfully measure blood glucose via glucometry and administer intranasal glucagon as necessary. The protocols and scope of practice need to be reviewed and updated. In addition, research should begin on intranasal administration of epinephrine, vasopressin and atropine to improve the abysmal rates of return-of-spontaneous-circulation and neurologically intact hospital discharge from cardiac arrest.

References

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Rob Curran, DC, EMT, has been an EMT in NYC for over 13 years and is an instructor of pathophysiology at the State University of New York-Downstate Medical Center. He can be reached at RPBDA@YAHOO.COM