Treating seizures with intranasal medications

Intranasal midazolam for acute seizure therapy

Introduction

Breakthrough seizures are all too commonplace in patients with epilepsy. Some of these seizures will prove to be prolonged. There are an estimated 150,000 cases of status epilepticus every year in the US.[1] Caretakers, prehospital and hospital providers are frequently faced with management of prolonged seizure activity. As morbidity and mortality are at least partially dependent on the duration of seizure activity it is crucial that seizures be stopped as soon as possible. Transmucosal delivery of benzodiazepines (midazolam or lorazepam) provides a very effective, safe and inexpensive means to rapidly achieve seizure control.

Seizures are to a certain degree self-sustaining. Because global central nervous system activity is a balance of excitatory and inhibitory neurotransmission factors that shift the balance toward excitation can lead to prolonged seizure activity. Many clinicians have noted through their practice experience that seizures seem to be self-reinforcing. A molecular explanation for this phenomenon is beginning to develop. Mounting evidence suggests that post-synaptic GABA_Areceptors are internalized during status epilepticus thereby reducing neuro-inhibition at the synapse.[2] The principle first-line agents for the treatment of status epilepticus are the benzodiazepines, which are GABA agonists. Therefore the longer a seizure persists the less effective this class of medicines may be suggesting that the earlier benzodiazepines are delivered the better.

Transmucosal delivery of generic benzodiazepines via the nasal mucosa offers an attractive and cost-effective alternative in the out-of-hospital setting. Midazolam and lorazepam easily cross the nasal mucosa and the blood brain barrier, resulting in a rapid rise in both the plasma and the cerebrospinal fluid concentrations.[3-6, 27]

Wermeling graph of midazolam concentrations when given IV, IN or IM

Wermeling et al. (2006) Pharmacokinetics and pharmacodynamics of a new intranasal midazolam formulation (25 mg/ml concentration) in healthy volunteers.[6]

Literature overview and discussion

Intranasal midazolam

Three randomized controlled trials and 1 prehospital observational trial exist, comparing rectal diazepam to either buccal (oral transmucosal) or intranasal midazolam.[7-10] Scott et al conducted a randomized controlled trial comparing buccal midazolam to rectal diazepam in epileptic students in an extended care school.[7] A school nurse administered medication to all students who suffered continuous seizures for more than a 5-minutes. Patients with persistent seizures for an additional 10 minutes were treated at the on-call physician’s discretion. Oral transmucosal midazolam was effective in 75% of cases (30 of 40 seizures), whereas rectal diazepam was effective in 59% (23/39) ( P = non significant). There were no adverse cardiorespiratory effects in either group. Although these differences did not achieve statistical significance, the trend toward a better outcome along with the more socially acceptable delivery of oral transmucosal medication led the school to change its preferred treatment to the oral transmucosal route.

Camfield et al found similar efficacy in their randomized trail comparing these 2 routes and drew identical conclusions—oral transmucosal midazolam was preferred over rectal diazepam because of ease of use and social acceptability.[8] The third randomized controlled trial, conducted by Fisgin et al, compared intranasal (rather than buccal) transmucosal midazolam to rectal diazepam.[9] In this study, midazolam aborted 20 (87%) of 23 seizures and rectal diazepam 13 (60%) of 22 seizures (P b .05). These results were statistically significant in favor of the intranasal 130 route when compared with the rectal route. Again, as in previous studies, no clinically important adverse events were identified in the 2 groups.

The final study, by Holsti et al, was conducted in a prehospital ambulance setting.[10] In this study, the entire emergency medical system converted from rectal diazepam to intranasal midazolam for treatment of pediatric seizures. The authors compared effectiveness and complication data before and after the change. The rates of prehospital seizure control (100% vs. 78%), need for 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 with the rectal diazepam group. The mean seizure duration was 11 minutes for those treated with nasal midazolam compared to 30 minutes for rectal diazepam. Children given the rectal medication were significantly more likely to have another seizure in the ED (odds ratio [OR] 8.4), need ED intubation (OR 12.2), need hospital admission (OR 29.3) and need ICU admission (OR 53.5).

All these authors conclude that trans-mucosal midazolam is more convenient, easier to use, just as safe, and is more socially acceptable than rectal diazepam. Furthermore, when given via the intranasal route, midazolam is more effective than rectal diazepam.

The above evidence clearly suggests that intranasal midazolam is superior to rectal midazolam for seizure therapy in children. However, IV benzodiazepines are first-line therapy in most hospitals—how does intranasal midazolam compare to IV benzodiazepines? Three randomized controlled trials comparing intranasal midazolam to IV diazepam answer this question.[11, 12, 26] Lahat et al compared intranasal midazolam to IV diazepam in children seizing 10 minutes or longer.[11] Patients were randomized to receive diazepam, 0.3mg/kg IV, or midazolam 0.2 mg/kg intranasally. Nasal midazolam stopped 23 (88%) of 26,whereas 24 (92%) of 26 were controlled with IV diazepam (P = non significant). The mean time from patient arrival to seizure cessation was 6.1 minutes with midazolam and 8.0 minutes with diazepam. The authors conclude that intranasal midazolam was as safe and effective as IV diazepam, but the overall time to cessation of seizures after arrival at the hospital was faster with intranasal midazolam because of the time required to establish an IV line in the diazepam group. A similar study was conducted by Mahmoudian and Zadeh.[12] These authors compared the efficacy of intranasal midazolam (0.2 mg/kg) to IV 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. Javadzadeh compared IV diazepam 0.3 mg/kg to intranasal midazolam 0.2 mg/kg in children suffering prolonged seizures.[26] (click here for free article) From time of drug delivery to cessation of seizure IV drug worked in 2.16 minutes while nasal worked in 3.16 minutes. However, due to delays related to establishing an IV, the time to control a seizure using IV diazepam was statistically and clinically significantly longer (6.42 minutes). Both therapies were 100% effective in the 60 patients treated. Thakker also conducted a randomized trial comparing IN midazolam to IV diazepam showing clinical equivalency in terms of seizure cessation but much faster resolution of the seizure when the nasal drug is given – all due to no need for an IV line. The time differences may be clinically significant in terms of brain hypoxia and potential long term outcomes – 6.7 minutes with nasal drug versus 17.2 minutes with IV therapy. In this study the resolution rates for single dose therapy were only 65 to 66% - very similar to other studies conducted outside of wealthy western countries (this study is from India). This is probably due to the very high incidence of CNS infections which was 26% in this study. Sharma and Harish provide yet another prospective study on the topic in 2013.[31] They randomized 100 children in their ER or NICU who were seizing to either intranasal midazolam or intravenous midazolam for the treatment of status epilepticus. As in every other prospective trial on the topic the two treatment are equivalent in terms of efficacy: In this study both were successful at stopping seizures 94% of the time with a single dose. The intranasal route was also slightly faster likely due to the delays associated with IV line establishment. Unique to this study was the inclusion of neonates: There were 7 neonates in this study and an additional 26 children under the age of 1 year. (Click here for free article)

All these authors conclude that nasal midazolam works faster, is safe, is easy to use and should be used not only in medical centers but also in general practitioners’ offices as well as at home by families of seizure-prone children after appropriate instruction. Evidence in the next paragraphs supports these conclusions.

Perhaps the greatest benefit of intranasal midazolam will be for the treatment of seizures in the prehospital, home or extended care setting. Wilson et al sent intranasal midazolam home with families of children suffering epilepsy and found that 33 of 40 (83%) who used it found it effective and 20/24 (83%) preferred using transmucosal midazolam to rectal diazepam.[13] Harbord reported experience using intranasal midazolam for home treatment of 54 seizures in 22 children.[14] These authors found it to be 89% effective, with no evidence of respiratory compromise. Ninety percent of families found no difficulty with nasal medication administration. Of the 15 parents with previous rectal diazepam experience, 13 thought intranasal delivery was easier and 14 preferred it to the rectal route. Jeannet et al, used intranasal midazolam both on the medical wards and as home therapy.[15] Their experience with 26 children suffering 125 seizures note a 98% effectiveness in under 10 minutes with no serious adverse effects. When compared to rectal diazepam they report that the intranasal route was both easier to use and that postictal recovery was faster. Scheepers et al report their experience with intranasal medication delivery in an extended care facility caring for adolescents and adults with severe epileptic disorders.[16] Of 84 uses, they found this route to be effective in 79 (94%). In the 5 instances when it was not effective, 3 of the 5 doses were delivered intra-orally rather than intranasally. In August 2010 Holsti published data from her prospective randomized trail comparing IN midazolam to rectal diazepam.[18] These authors trained 358 families to use nasal midazolam and rectal diazepam. They then randomized the families to one or the other therapies to be administered only if seizures lasted over 5 minutes. There were 92 patients treated - 50 with nasal and 42 with rectal drug. Seizure control was slightly faster with nasal drug (3 vs. 4.3 minutes) and was preferred by parents in terms of ease of administration and overall satisfaction. It was felt to be considerable less expensive and more cost effective (though the felt cost studies should be formally conducted.)

Holsti, Intranasal midazolam versus rectal diazepam for home treatment of seizure in children (click here for link to the article)

Video presentation of the Holsti home intranasal midazolam for seizures data (click here)

Kay et al demonstrated a reduction in recurrent seizure activity for 24 hours in patients undergoing video EEG monitoring who were given IN midazolam to treat any seizure noted during the procedure.[39] This same author later investigated IN midazolam as first line treatment of status epilepticus on the neuro ward and found it effective in about 5 minutes on 57% of these complex cases, suggesting it is a good first line treatment in this setting or any setting where no IV is available.[53] Owusu et al found that even if an IV is available, intranasal midazolam was just as effective in adults with prolonged seizures or clusters of seizures. They compared the efficacy of IV lorazepam (1-2 mg) to Intranasal midazolam (Generic - 3 mg or 0.6 ml atomized) in adult epilepsy patients suffering acute (> 5 min) or cluster seizures (> 3 in 30 min) being monitored in an epilepsy unit. They found that IN midazolam was equivalent in efficacy but much easier to administer and the need for maintaining an IV on the unit was eliminated. They have eliminated IV lorazepam from their rescue medication and converted to IN Midazolam.[55]

A 2010 review on the topic concluded that midazolam by any route - specifically IN or buccal - is superior to diazepam by any route (including IV) for the treatment of status epilepsy.[19] However, at about the same time, another article was published that compared IN midazolam (10 mg) to rectal diazepam (10 mg) in 21 adults suffering 124 different seizures and no difference in efficacy or time to effect was found. Never the less - 16 of 21 caregivers and the patient preferred nasal midazolam over rectal diazepam.[20]

In 2013 Veldhorst-Janssen published a PhD thesis on intranasal drug delivery.[29] This was a study interviewing adult epileptics regarding their preference for nasal versus rectal drug to treat their recurrent seizures. Despite pretty apparent increase in efficacy (75 vs. 55 on a 100 point scale of preference), impression of better convenience (71 vs. 58) and overall global satisfaction (68 vs. 56) with the nasal drug, the sample size of 25 patients did not provide the statistical power to prove preference. Interestingly they also found that the side effect profile of the rectal drug was preferred. However, there are profound differences in the two study groups in terms of frequency of seizures, educational background, etc. so most of these conclusions are suspect. Never the less – here is a study showing nasal midazolam is useful in adults though I suspect they used a higher concentration than the generic IV formulation.

Adult patient satisfaction with rectal diazepam versus nasal midazolam

Graph showing Adult patient satisfaction with rectal diazepam versus nasal midazolam [29]

Click here for the PDF downloaded from the free thesis link

Also in 2013, Humphries and Eiland wrote a review of intranasal midazolam for the treatment of acute seizures.[30] The article provides a very nice up to date overview of the pharmacokinetics and absorptive properties of benzodiazepines for anyone who is interested. They also provide an extensive review of the literature regarding the two currently available rapid methods of treating seizures in an outpatient setting – rectal diazepam versus nasal midazolam – including cost differences (a few hundred dollars for ONE DOSE for rectal versus less than 20 dollars a dose for nasal). They conclude that “Intranasal midazolam should be considered as an anticonvulsant agent for community, prehospital, and ED use in children when intravenous access is not available and the rectal route is not desirable.” (Click here for link to FREE ARTICLE)

In 2015, Bancke et al found that a commercially reformulated form of IN midazolam shows superior bioavailability, though this does not necessarily translate into improved clinical outcomes nor does it imply affordability.[42]

In 2015 another review in the form of a meta-analysis was published on this topic. Brigo et al published a meta-analysis of 1933 seizure episodes entered into all the high quality studies the authors selected that statistically verifies what has been stated on this site for the last 7 years and which we have used in our community for the last 18 years: Non-IV midazolam (i.e. Intranasal or buccal) is just as effective at stopping seizures as IV or rectal diazepam but its onset of action and cessation of seizures is faster due to the rapidity of delivery.[40] Other review studies come to similar conclusions.[44,46, 47] (These studies and my practice location are in the Western world where most seizures are NOT due to meningitis – IN therapy may not be as effective as IV therapy in Africa where cerebral malaria and bacterial meningitis is so common as has been noted in other studies reviewed on this web site). Some authors do point out that that rectal and buccal benzodiazepines are not ideal methods of delivery of drugs due to unpredictable absorption. They prefer IN or IM delivery for better reliability and they call for more adult studies.[48]

Intranasal midazolam for seizure control is now entering numerous status epilepsy protocols.[34,50] In patients with brain tumors near the end of life it is often difficult for them to take anything by mouth. For that reason IN midazolam is suggested as a method for controlling their seizures and improving their quality of life.[35]

Crawford et al provide an overview of IN midazolam use and ideas for implementation in a community practice.[43] The article is packed full of data that essentially mirrors what is stated in this web site: When comparing IN midazolam to rectal diazepam for outpatient treatment of status epilepticus the IN route is more effective, costs much less, results in better outcomes (shorter seizure time, less admission to hospital), has less of a social stigma and is markedly preferred by families of the epileptic patient. Based on this information the authors attempted to change practice in their medical community and transition their neurologic practice over to prescribing IN midazolam as the preferred outpatient rescue medication and make it available from local pharmacies. They note very rapid adoption in the practice after presenting detailed information and setting up local pharmacies with delivery devices and appropriate drugs. Further challenges involved school nurse education when children showed up with a new drug delivery system. This paper addresses this and many challenges and should be read by any clinician who anticipates adopting IN benzodiazepine use in their community. Its conclusions related to educating the community are echoed by Terry et al who found school nurses to be relatively un-informed regarding intranasal medications to seizure therapy.[45]

Nunley et al compared healthcare utilization rates in 5458 children who were using either intranasal midazolam or rectal diazepam (or both) to treat acute seizures. They found a significant reduction in ED visits, urgent care visits and ambulance transports in children using IN midazolam over those using rectal diazepam. They conclude that their results “substantiate the cost-effective benefits of prescribing intranasal midazolam compared to per rectum diazepam”. [51] The same author published a study looking at caregiver preferences and overwhelmingly confirmed the preference and impression of ease of use and of efficacy for IN midazolam over rectal diazepam.[54]

Crawshaw and Cock have put transmucosal benzodiazepines into their status epilepticus algorithm as the first line therapy in patients without an IV stating “Speed of administration and adequate initial dosing are probably more important than the choice of drug.” [59] (Free access on internet – click here for PDF)

Interestingly, despite all these papers showing strong preference by the end user and at least equivalent or superior efficacy - most pediatric neurologists in 2018 still prescribed far more rectal diazepam than nasal midazolam.[57] Change is hard, especially when there is not a pharmaceutical rep pushing you into their expensive drug.

The EMS system in Zurich Switzerland had a shortage of IV lorazepam so they tested IN midazolam single dose (the dose is unknown to this writer) and IV diazepam on their adult seizure patients. They found IN midazolam in one dose to be effective in terminating seizures in 57% of adults suffering status epilepticus – good first line results in patients without an IV but not ideal or as high as the 85-90% seen in children. For that reason they still establish IV lines in the adults and follow-up with IV medications if needed.[56] Perhaps a higher dose or a more concentrated midazolam solution will result in similar seizure control in adults as has been the case in kids.[58]

Intranasal Lorazepam

Intranasal lorazepam, another anti-seizure medication, also appears effective and safe for treating status epilepsy based on a single trial. A large study conducted in rural Africa compared intranasal lorazepam to intramuscular paraldehyde (a common medication used in the third world to seizure therapy) in 160 patients, most of whom were seizing for an extended time period (mean seizure duration was over 2 hours).[17] Despite these prolonged seizures, intranasal lorazepam managed to stop three quarters of the seizures in a few minutes, while intramuscular medication only worked 61% of the time. There were no respiratory side effects seen with the lorazepam.

This same group of researchers then designed a study to compare IN lorazepam to buccal lorazepam and IV lorazepam. Their goal was to prove that these non-invasive routes of administration were just as effective as the "gold standard" IV delivery route yet easier to deliver and not requiring any shot or skill set required to deliver the shot. Interestingly and unfortunately they had to stop the study because on interim analysis of the data they found the buccal route (but not the nasal route) was more than 30% less effective than the other routes. You can see the study design and comments on termination at this web site link: http://clinicaltrials.gov/ct2/show/NCT00343096

Editorial comment: This is a recurring finding in the acute pain literature and now in the seizure literature - buccal drug delivery results in lower drug levels and peaks later than nasal drug delivery so it is not ideal for treating medical problems that require rapid onset of action. Fortunately other researchers have done similar studies without the buccal arm and shown that nasal delivery is indeed as effective as IV lorazepam delivery for actually stopping seizures - see below.

However, by 2015 it appeared they persevered, or at least took the data they had and published it in an African medical journal:

Lissauer et al conducted a prospective open label randomized trial in African children suffering status epilepsy to determine whether lorazepam (0.1 mg/kg) given via the IV, IN or buccal route was superior.[38] They found seizures were controlled within 10 minutes in 46% of the buccal group, 57% of the nasal group and 83% of the IV group. These results are not surprising when one looks at their patient population: Over 10% had HIV, over 50% had malaria, many seizures lasted hours prior to treatment, most patients did not have idiopathic epilepsy (<17%), over 25% had cerebral malaria and an additional 15-20% had bacterial meningitis, 15-20% died. As often stated in this web site, nasal drug delivery is simply another tool for delivering anti-seizure medications rapidly while IV therapy is a higher “gold standard” in many clinical settings and should be established based on patient severity of illness. Were I to work in this clinical setting I would very rapidly move to establishing an IV in any seizure patient seen here given the populations illness severity. Unless you work in a setting where seizures are a marker of such severe infectious illness, you cannot extrapolate these results to your practice. These authors concur and state that in their clinical setting, the IV route is superior but transmucosal drug delivery (buccal, nasal) should be implemented when IV access cannot be rapidly obtained.

click here for the article (free)

In January of 2012, Anderson et al published a study that explains why buccal lorazepam was inferior to nasal midazolam.[23] Using a crossover design volunteer study they found that buccal drug does not absorb as rapidly as nasal drug and so is not as clinically effective for disease states that require rapid onset of action (seizure, breakthrough pain, opiate reversal for examples). Nasal lorazepam achieves therapeutic levels in the blood and CSF more rapidly and therefore its clinical onset of action is earlier. The diagram below shows resulting serum levels in the first 10 minutes.

Anderson et al diagram showing serum levels of intranasal lorazepam versus buccal lorazepam in the first 10 minutes following delivery

The authors make the following conclusions: "The results from the present study suggest that the intranasal administration route leads to a significantly faster detectable concentration of lorazepam in plasma than the buccal route for the termination of prolonged seizures. Our findings suggest that intranasal, rather than buccal, lorazepam is likely to be more appropriate for the management of children with acute seizures."

In February of 2011 a potentially practice changing article was published on the topic.[21] The authors conducted a randomized trial comparing what many of us consider the gold standard for status epilepticus initial therapy - IV lorazepam, to the same dose of lorazepam given intranasally. The results showed identical efficacy and identical suppression of recurrent seizures over the next hour. Not mentioned in the abstract is the fact that the results are based on seizure control from the time of drug administration. They admit the nasal drug was given "virtually instantaneously" whereas the IV drug took between 1 and 25 minutes (median 4 minutes) to administer (due to difficulty of experience pediatric clinicians successfully starting an IV in a seizing child). This concept needs to be studied further in adults - lorazepam is more potent than midazolam and may be a better drug for both seizure control and excited delirium control in a full grown adult due to this potency difference.

Click here for a thoughtful editorial written by Dr. Jacqueline French [22] on this IN lorazepam article: French, Benzo vs. Benzo: And the winner is...., Epilepsy Curr 2011

Another study and its accompanying editorial of importance to this discussion were published in the New England Journal of Medicine in February 2012.[24, 25] While this study does not actually use intranasal medications to treat seizures, it is a very important and well done trial that is applicable to the discussion regarding therapy for status epilepsy. These authors found that intramuscular midazolam was as good if not better than intravenous lorazepam for rapid termination of status epilepsy. The reason is due to ease of drug delivery and therefore rapid drug delivery. Of course this is also the reason that intranasal midazolam and lorazepam are as effective as intravenous benzodiazepines in all the studies reviewed here. For some reason they make a very odd comment supported by absolutely no data - "Midazolam can be administered by other non-intravenous routes as well, but the intramuscular route is more consistently effective than the intranasal or buccal routes because the drug cannot be blown or spat out by the convulsing patient." This is not true. First of all, the literature suggests otherwise and the editorial in the same issue of the NEJM points out 3 reference showing IM benzodiazepines absorb LESS rapidly than nasal drugs (two references can be found in the seizure section of this web site - O'Regan 1996, Wermeling 2009). Secondly, this statement shows the lack of experience of the authors who wrote it - IN drugs are very easy to deliver to a seizing patient if you use a syringe driven atomizer and the patient is unconscious so they can't spit it back at your. Finally, many other studies for other drugs like opiates show more rapid onset of action and much higher patient satisfaction with IN versus IM drugs so I am not sure why these authors or the NEJM editorialist would allow this opinion to be stated. Never this less, this is a great study that demonstrates non intravenous therapy is essentially as effective as IV delivery of benzodiazepines for treatment of seizures and it is a lot easier to administer. It will be interesting to find out what the final version of this therapy costs. Currently the only FDA approved drug for out-patient seizure therapy is rectal diazepam and it costs well over $200-300 per dose in a U.S. pharmacy while being much less effective than nasal, intramuscular or intravenous therapy. Given this current cost, this new therapy will likely demand a similar price. Our EMS system, local emergency departments and our community pediatric neurologists use generic midazolam as first line therapy in the EMS, ER and outpatient setting - at about $2-3 per dose plus a few dollars for the delivery device. They have used this therapy for almost a decade and their success rates are similar or superior to those found in this study.[10,18]

Intranasal Diazepam

Although early data demonstrated poor bioavailability of nasal diazepam, the pharmaceutical industry has recognized an opportunity for nasal benzodiazepines and we are in the midst of research with modified diazepam molecules to make them more available via the nasal mucosa.[36] There is a plethora of older data on this but as of 2014 it appears to be more mature so it is time to begin providing recent literature on this topic.

Henney et al found a modified IN diazepam formulation (enhanced for nasal delivery) similar in terms of bioavailability as rectal diazepam gel. They believe this offers caregivers and patients a more socially acceptable and convenient method for treating seizures.[32]

Inokuchi et al retrospectively compared their experience using intranasal diazepam or intravenous diazepam for controlling status epilepsy in acute stroke patients presenting to their institution.[37] They found IN drug was delivered 9 times faster ( 1 vs. 9 minutes) and seizure control occurred three times faster (3 versus 9.5 minutes). They conclude “Intranasal diazepam administration is safer, easier, and quicker than intravenous administration.”

Costs of care:

Caron et al conducted a study that quantified the CHARGES (not cost) for pediatric seizure care of 90 patients who discharged home from a US hospital emergency room.[40] The average charge was $2444 with a range of $370 to $17126. The authors state they provide this data so clinicians can understand the costs and compare the values of various treatment options (like home rectal diazepam or IN midazolam). (It should be noted that at the end of this section of the website protocols with teaching materials are available that provide you clinicians with a method to provide effective and safe home care at about 12 dollars or less per treatment and which the literature notes to be 90% effective – thereby allowing the family to stay home and save the $2444 as well as the ambulance charges).

Sanchez Fernandez utilized published data on seizure cessation with various delivery methods (Nasal, buccal, IM, and rectal benzodiazepines) and then obtained available market prices of each of these medications.[49] They found that nasal and buccal midazolam are the most cost effective methods and that rectal diazepam is never cost effective given it lower efficacy and markedly higher price (50 times more expensive and less effective). Interestingly, they point out that rectal diazepam does NOT have regulatory approval for treating ongoing seizures or status epilepticus. Instead it is approved just for reducing frequency of seizures and its place in status epilepticus treatment algorithms is off label and is very questionable given its poor performance in these situations. For these reasons, rectal diazepam is no longer recommended for use in status epilepsy by the American epilepsy society – rather they recommend non-IV midazolam delivery methods.

Sanchez drug costs for epilepsy

Sanchez graph of cost vs efficacy for seizure meds

The table and graph above shows the parameters Sanchez Fernandez et al used to determine their results: Cost is the total cost of the drug plus applicator (nasal atomizer or syringe and needle etc). Effectiveness is the literature reported percentage of cases (from 24 studies reviewed) that the medication and delivery route will stop prolonged seizures. The graph plots the cost versus the effectiveness with the ideal drug being one that plots out at the lower right corner of the graph (low cost, highly effective). As is readily apparent rectal diazepam is an absolute outlier.

Ostendorf et al reported the results of a QI project focusing on reducing time to status epilepsy treatment in their hospital with a focus on intranasal midazolam over IV lorazepam. Their efforts paid off with a reduction in time to treatment from 14 minutes to 7.5 minutes while also decreasing percentage of transfers to the ICU from 39% to 9% - resulting in 2.1 million dollar reductions in hospital charges.[52]

Conclusion:

This data is fairly compelling. Multiple studies from different authors throughout the world confirm that intranasal midazolam (and in now IN lorazepam) is a safe and very effective means to achieve seizure control at home, in the ambulance and in the hospital. Its rapid onset of action, social acceptability, ease of use and efficacy suggest that this therapy should be adopted in appropriate situations (prolonged seizures) where IV access is not immediately available.

Personal insights from experienced clinicians

Tom Macfarlane, MD. Emergency Physician, Salt Lake City, Utah:

I have extensive experience in using intranasal midazolam in the hospital and home settings. As an emergency physician I frequently care for patients who are experiencing seizures. It is often difficult to establish intravenous access in these seizing patients and therefore transmucosal drug delivery is a great option. I also have a 4 year-old son who experiences frequent prolonged seizures. My family and I have safely administered over 60 transmucosal doses of midazolam over the course of 3 years. This has allowed us to avoid many trips to the Emergency Department and provides us with a degree of increased freedom. I am confident that my son would not be functioning at the level he is today without intranasal midazolam.

Margaret Krykou , MD- South Australian physician discussing experience with in home use of intranasal midazolam:

Article she wrote on IN midazolam use in the community (Click Here)

Treatment protocol:

Note: Midazolam is now available in prefilled syringes. Just connect an atomizer and deliver the correct dose.

Prefilled syringes of medication:

Based on extensive research and community use, prepackaged midazolam in the 5mg/ml dosing would certainly seem appropriate for use by properly trained families and BLS providers - and this packaging would surely help improve the ease of use. See this PDF file for the information on many prepackaged medications including midazolam and lorazepam: Carpuject medications In situations where the entire volume might not be appropriate (smaller child), the syringe can have a indelible mark or piece of tape applied by the clinician or pharmacy at the appropriate dosage so the parent/provider knows how much to give. Just be sure to use the proper concentration.

Carpuject of midazolam (has a Luer attachment for a needle or atomizer)

Carpuject of midazolam

Intranasal midazolam for acute seizures

Indications: For treatment of persistent seizure activity

Procedure:

Assess ABC’s – Airway, Breathing, Circulation
For pulseless patients, proceed to ACLS guidelines
Apply 100% oxygen NRB mask to seizing patient
Use age based table to determine proper volume of midazolam for atomization (see table below)
To calculate it manually, use the below formula
- Assess weight: children weight in kg = 10 + 2(Age in years)
- Calculate appropriate dose of midazolam using the following formula:
  - Children: Total kg wt X 0.2 mg = total mg dose of midazolam, maximum of 10 mg
  - Adults over 50 kg: 10 mg (2 ml) of midazolam
  - Total volume in milliliters of midazolam (5mg/ml concentration) = (Total mg dose divided by 5mg/ml) + 0.1 ml for dead space of device.
(If using lorazepam - 0.1 mg/kg to max 4 mg)
Load syringe with appropriate milliliter volume of midazolam (use only 5mg/ml concentration) and attach nasal atomizer
Place atomizer within the nostril
Briskly compress syringe to administer 1/2 of the volume as atomized spray.
Remove and repeat in other nostril, so all the medication is administered
Continue ventilating patient as needed
If seizures persist 5 minutes after treating, consider repeating ½ dose of midazolam either intranasally, intramuscularly or intravenously. Secure airway if necessary.

Midazolam Dosing chart

Patient age (years)	Weight (kg)	IN Midazolam volume in ml* 5mg/ml concentration Volume Dose (mg)
Neonate	3 kg	0.3 ml 0.6 mg
<1 yr	6 kg	0.4 ml 1.2 mg
1 yr	10 kg	0.5ml 2.0 mg
2 yr	14 kg	0.7 ml 2.8 mg
3 yr	16 kg	0.8 ml 3.2 mg
4 yr	18 kg	0.9 ml 3.6 mg
5 yr	20 kg	1.0 ml 4.0 mg
6 yr	22 kg	1.0 ml 4.4 mg
7 yr	24 kg	1.1 ml 4.8 mg
8 yr	26 kg	1.2 ml 5.2 mg
9 yr	28 kg	1.3 ml 5.6 mg
10 yr	30 kg	1.4 ml 6.0 mg
11 yr	32 kg	1.4 ml 6.4 mg
12 yr	34 kg	1.5 ml 6.8 mg
Small teenager	40 kg	1.8 ml 8.0 mg
Adult or full-grown teenager	> 50 kg	2.0 ml 10.0 mg

* This volume is based on the calculated dose PLUS 0.10 ml dead space in the device (the amount of medication that will remain within the syringe and atomizer tip and therefore will not be delivered to the child). The total volume is then rounded off to the next highest 0.1 ml. Slightly higher doses may be appropriate at the lower range of volume (in smaller children) due to measurement difficulties and possible under dosing which may not stop the seizure.

In some children a higher dose (0.3 mg/kg) may be more appropriate

Teaching materials

Video of a family successfully treating their seizing child with intranasal midazolam in a city park

Quick time download file for teaching (click here)

Home therapy for seizures:

EMS seizure therapy protocols (Click here)

Peer Reviewed full articles open access from publisher

Klein-Kremer, Intranasal midazolam for the treatment of seizures in children in the Emergency setting, Isreali J EM 2007 (click here) - PDF 0.13 MB

Lahat, IN midazolam for seizures, BMJ 2000 (click here) - PDF 0.25 MB

Krykou, IN midazolam for community seizure therapy, Epilepsy Australia 2006 (click here) - PDF 0.44 MB

Ma, Clinical Guidelines on Management of Prolonged Seizures, HK J Paediatrics 2010 - MS word filed

Segal, An alternate route of drug administration in acute convulsions, IMAJ 2000 (click here) - PDF 0.09 MB

Javadzadeh, M., K. Sheibani, et al. (2012). "Intranasal midazolam compared with intravenous diazepam in patients suffering from acute seizure: A randomized controlled trial." Iran J Pediatr (click here)

Lissauer, S., J. Kenny, et al. (2015). "Buccal, intranasal or intravenous lorazepam for the treatment of acute convulsions in children in Malawi: An open randomized trial." African Journal o f Emergency Medicine 5: 120-126.

Bibliography (click here for abstracts)

1. DeLorenzo, R.J., et al., Epidemiology of status epilepticus. J Clin Neurophysiol, 1995. 12(4): p. 316-25.

2. Goodkin, H.P., J.L. Yeh, and J. Kapur, Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci, 2005. 25(23): p. 5511-20.

3. Wermeling, D.P., et al., Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol, 2001. 41(11): p. 1225-31.

4. Knoester, P.D., et al., Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers. Br J Clin Pharmacol, 2002. 53(5): p. 501-7.

5. Malinovsky, J.M., et al., Plasma concentrations of midazolam after i.v., nasal or rectal administration in children. Br J Anaesth, 1993. 70(6): p. 617-20.

6. Wermeling, et al., Pharmacokinetics and pharmacodynamics of a new intranasal midazolam formulation in healthy volunteers. Anesth Analg, 2006. 103(2): p. 344-9, table of contents.

7. Scott, R.C., F.M. Besag, and B.G. Neville, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet, 1999. 353(9153): p. 623-6.

8. Camfield, P.R., Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. J Pediatr, 1999. 135(3): p. 398-9.

9. Fisgin, T., et al., Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study. J Child Neurol, 2002. 17(2): p. 123-6.

10. Holsti, M., et al., Prehospital intranasal midazolam for the treatment of pediatric seizures. Pediatr Emerg Care, 2007. 23(3): p. 148-53.

11. Lahat, E., et al., Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. Bmj, 2000. 321(7253): p. 83-6.

12. Mahmoudian, T. and M.M. Zadeh, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav, 2004. 5(2): p. 253-5.

13. Wilson, M.T., S. Macleod, and M.E. O'Regan, Nasal/buccal midazolam use in the community. Arch Dis Child, 2004. 89(1): p. 50-1.

14. Harbord, M.G., et al., Use of intranasal midazolam to treat acute seizures in paediatric community settings. J Paediatr Child Health, 2004. 40(9-10): p. 556-8.

15. Jeannet, P.Y., et al., Home and hospital treatment of acute seizures in children with nasal midazolam. Eur J Paediatr Neurol, 1999. 3(2): p. 73-7.

16. Scheepers, M., et al., Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy? Seizure, 2000. 9(6): p. 417-22.

17. Ahmad, S., et al., Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial. Lancet, 2006. 367(9522): p. 1591-7.

18. Holsti, M, et al: Intranasal midazolam versus rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med 2010;164(8):747-753. (click here for full article link)

19. McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med 2010;17(6):575-82.

20. de Haan GJ, van der Geest P, Doelman G, Bertram E, Edelbroek P. A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations. Epilepsia 2010;51(3):478-82.

21. Arya, R., S. Gulati, et al. (2011). "Intranasal versus intravenous lorazepam for control of acute seizures in children: A randomized open-label study." Epilepsia.

22. French JA.. Benzo vs Benzo: And the winner is.. Epilepsy Curr 2011;11(5):143-144 (click here for the open access article)

23. Anderson, M., et al., Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers. Eur J Clin Pharmacol, 2012. 68(2): p. 155-9.

24. Silbergleit, R., et al., Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med, 2012. 366(7): p. 591-600.

25. Hirsch, L.J., Intramuscular versus intravenous benzodiazepines for prehospital treatment of status epilepticus. N Engl J Med, 2012. 366(7): p. 659-60.

26. Javadzadeh, M., K. Sheibani, et al. (2012). "Intranasal midazolam compared with intravenous diazepam in patients suffering from acute seizure: A randomized controlled trial." Iran J Pediatr 22(1): 1-8. (Click here for open access to the article)

27. Hardmeier, M., R. Zimmermann, et al. (2012). "Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers." Clin Pharmacol Ther 91(5): 856-862.

28. Thakker, A. and P. Shanbag (2012). "A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures." J Neurol.

29. Veldhorst-Janssen, N. M. (2013). Intranasal delivery of rapid acting drugs: Studies of pharmacokinetics, effect, tolerability and satisfaction, Universitaire Pers Maastricht. PhD Thesis: 141: Patient satisfaction with intranasal midazolam versus rectal diazepam as fast-working recue medication in epilepsy. Click here for the PDF

30. Humphries, L. K. and L. S. Eiland (2013). "Treatment of acute seizures: is intranasal midazolam a viable option?" J Pediatr Pharmacol Ther 18(2): 79-87. (click here for PDF)

31. Sharma, R. and R. Harish (2013). "Comparative study of the efficacy of intranasal midazolam vs intravenous midazolam in convulsing neonates and children." RRJMHS 2(4): 54-57. (click for free article)

32. Henney, H.R., 3rd, et al., Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults. Epilepsy Res, 2014. 108(7): p. 1204-11.

34. Lagae, L., Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures. Epileptic Disord, 2014. 16 Suppl 1: p. 44-9

35. Koekkoek, J.A., M.S. Boddaert, and M. Taphoorn, [Gliomas: fighting until the end against epilepsy; administration of antiepileptic drugs in the end-of-life phase]. Ned Tijdschr Geneeskd, 2014. 158(1): p. A6924.

36. Sperling, M.R., et al., Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy. Epilepsia, 2014. 55(10): p. 1544-50.

37. Inokuchi, R., N. Ohashi-Fukuda, et al. (2015). "Comparison of intranasal and intravenous diazepam on status epilepticus in stroke patients: a retrospective cohort study." Medicine (Baltimore) 94(7): e555.

38. Lissauer, S., J. Kenny, et al. (2015). "Buccal, intranasal or intravenous lorazepam for the treatment of acute convulsions in children in Malawi: An open randomized trial." African Journal o f Emergency Medicine 5: 120-126.

39. Kay, L., P. S. Reif, et al. (2015). "Intranasal midazolam during presurgical epilepsy monitoring is well tolerated, delays seizure recurrence, and protects from generalized tonic-clonic seizures." Epilepsia.

40. Brigo, F., R. Nardone, et al. (2015). "Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis." Epilepsy Behav.

41. Caron, E., C. E. Wheless, et al. (2015). "The charges for seizures in the pediatric emergency room: a single center study." Pediatr Neurol 52(5): 517-520.

42. Bancke, L. L., H. A. Dworak, et al. (2015). "Pharmacokinetics, pharmacodynamics, and safety of USL261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers." Epilepsia 56(11): 1723-1731.

43. Crawford, D. (2016). "Implementation of Intranasal Midazolam for Prolonged Seizures in a Child Neurology Practice." J Neurosci Nurs.

44. Haut, S. R., S. Seinfeld, et al. (2016). "Benzodiazepine use in seizure emergencies: A systematic review." Epilepsy Behav 63: 109-117.

45. Terry, D., A. D. Patel, et al. (2016). "Barriers to Seizure Management in Schools: Perceptions of School Nurses." J Child Neurol.

46. Zelcer, M. and R. D. Goldman (2016). "Intranasal midazolam for seizure cessation in the community setting." Can Fam Physician 62(7): 559-561.

47. Alshehri, A., A. Abulaban, et al. (2017). "Intravenous Versus Nonintravenous Benzodiazepines for the Cessation of Seizures: A Systematic Review and Meta-analysis of Randomized Controlled Trials." Acad Emerg Med 24(7): 875-883.

48. Mula, M. (2017). "New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective." CNS Drugs 31(1): 11-17.

49. Sanchez Fernandez, I., M. Gainza-Lein, et al. (2017). "Nonintravenous rescue medications for pediatric status epilepticus: A cost-effectiveness analysis." Epilepsia 58(8): 1349-1359.

50. Maglalang, P. D., D. Rautiola, et al. (2018). "Rescue therapies for seizure emergencies: New modes of administration." Epilepsia 59 Suppl 2: 207-215.

51. Nunley, S., P. Glynn, et al. (2018). "Healthcare Utilization Characteristics for Intranasal Midazolam Versus Rectal Diazepam." J Child Neurol 33(2): 158-163.

52. Ostendorf, A. P., K. Merison, et al. (2018). "Decreasing Seizure Treatment Time Through Quality Improvement Reduces Critical Care Utilization." Pediatr Neurol 85: 58-66.

53. Kay, L., N. Merkel, et al. (2019). "Intranasal midazolam as first-line inhospital treatment for status epilepticus: a pharmaco-EEG cohort study." Ann Clin Transl Neurol 6(12): 2413-2425.

54. Nunley, S., P. Glynn, et al. (2019). "A hospital-based study on caregiver preferences on acute seizure rescue medications in pediatric patients with epilepsy: Intranasal midazolam versus rectal diazepam." Epilepsy Behav 92: 53-56.

55. Owusu, K. A., M. B. Dhakar, et al. (2019). "Comparison of intranasal midazolam versus intravenous lorazepam for seizure termination and prevention of seizure clusters in the adult epilepsy monitoring unit." Epilepsy Behav 98(Pt A): 161-167.

56. Theusinger, O. M., P. Schenk, et al. (2019). "Treatment of Seizures in Children and Adults in the Emergency Medical System of the City of Zurich, Switzerland - Midazolam vs. Diazepam - A Retrospective Analysis." J Emerg Med 57(3): 345-353.

57. Wallace, A., E. Wirrell, et al. (2019). "Seizure Rescue Medication Use among US Pediatric Epilepsy Providers: A Survey of the Pediatric Epilepsy Research Consortium." J Pediatr 212: 111-116.

58. Detyniecki, K., P. J. Van Ess, et al. (2019). "Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters-a randomized, double-blind, placebo-controlled trial." Epilepsia 60(9): 1797-1808.

59. Crawshaw, A. A. and H. R. Cock (2020). "Medical management of status epilepticus: Emergency room to intensive care unit." Seizure 75: 145-152. (Free access on internet – click here for PDF)

Therapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

Concepts:

Clinical-Uses:

Education: