Therapeutic
Intranasal Drug DeliveryIntranasal midazolam or lorazepam for acute seizure treatment - abstracted references:
(2000). "Intranasal midazolam effectively treats
febrile seizures in children." Bmj 321(7253): D.
Ahmad, S., J. C. Ellis, et al. (2006). "Efficacy
and safety of intranasal lorazepam versus intramuscular paraldehyde for
protracted convulsions in children: an open randomised trial." Lancet
367(9522): 1591-7.
BACKGROUND: In sub-Saharan Africa, rectal diazepam or intramuscular paraldehyde are commonly used as first-line anticonvulsant agents in the emergency treatment of seizures in children. These treatments can be expensive and sometimes toxic. We aimed to assess a drug and delivery system that is potentially more effective, safer, and easier to administer than those presently in use. METHODS: We did an open randomised trial in a paediatric emergency department of a tertiary hospital in Malawi. 160 children aged over 2 months with seizures persisting for more than 5 min were randomly assigned to receive either intranasal lorazepam (100 microg/kg, n=80) or intramuscular paraldehyde (0.2 mL/kg, n=80). The primary outcome measure was whether the presenting seizure stopped with one dose of assigned anticonvulsant agent within 10 min of administration. The primary analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00116064. FINDINGS: Intranasal lorazepam stopped convulsions within 10 min in 60 (75%) episodes treated (absolute risk 0.75, 95% CI 0.64-0.84), and intramuscular paraldehyde in 49 (61.3%; absolute risk 0.61, 95% CI 0.49-0.72). No clinically important cardiorespiratory events were seen in either group (95% binomial exact CI 0-4.5%), and all children finished the trial. INTERPRETATION: Intranasal lorazepam is effective, safe, and provides a less invasive alternative to intramuscular paraldehyde in children with protracted convulsions. The ease of use of this drug makes it an attractive and preferable prehospital treatment option.
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.
BACKGROUND: The acquisition of intravenous (IV) access in the
actively convulsing patient is difficult. This often delays the
administration of the IV benzodiazepine (BDZ) necessary for seizure
cessation. Delays in seizure cessation are associated with increased
pharmacoresistance, increased risk of neuronal injury, worse patient
outcomes, and increased morbidity. OBJECTIVE: The objective was to
assess whether the delay imposed by IV access acquisition is justified
by improved outcomes. We compared IV versus non-IV BDZ efficacy in the
real world with regard to failure rates (primary outcome), interval to
seizure control, and observed complications (secondary outcomes).
METHODS: A systematic review was performed using Medline, Embase, and
the Cochrane Library. All studies published or in press from the
inception of the respective database to July 2016 were included. Only
randomized and quasi-randomized controlled trials directly comparing IV
to non-IV (buccal, rectal, intranasal, or intramuscular) BDZ were
included. RESULTS: Our search strategy retrieved 2,604 citations for
review. A total of 11 studies were finally included in qualitative
synthesis and 10 in quantitative analysis. Only one was of high quality.
For treatment failure, non-IV BDZ was superior to IV BDZ (odd ratio [OR]
= 0.72; 95% confidence interval [CI] = 0.56-0.92). However, no
significant difference was found between the two treatments in the
pediatric subgroup (OR = 1.16; 95% CI = 0.74-1.81). Non-IV BDZ was
administered faster than IV BDZ and therefore controlled seizures faster
(mean difference = 3.41 minutes; 95% CI = 1.69-5.13 minutes) despite a
longer interval between drug administration and seizure cessation (mean
difference = 0.74 minutes; 95% CI = 0.52-0.95 minutes). Respiratory
complications requiring intervention were similar between non-IV BDZ and
IV BDZ, regardless of administration route (risk difference = 0.00; 95%
CI = -0.02 to 0.01). CONCLUSION: Non-IV BDZ, compared to IV BDZ,
terminate seizures faster and have a superior efficacy and side effect
profile. Higher-quality studies and further evaluation in different age
groups are warranted.
Anderson, M., P. Tambe, et al. (2012). "Pharmacokinetics of buccal and
intranasal lorazepam in healthy adult volunteers." Eur J Clin
Pharmacol 68(2):
155-159.
PURPOSE: To investigate the plasma-concentration profile of
lorazepam when administered by the intranasal and buccal routes to
determine their utility for the treatment of prolonged seizures.
METHODS: On two occasions separated by at least 7 days washout, 12
healthy adult male volunteers received 2 mg of lorazepam via the
intranasal or buccal route. Blood samples were collected at time periods
from 0 to 48 h, and pharmacokinetic parameters were determined. RESULTS:
Lorazepam was well absorbed from both administration routes; however,
there was a more pronounced lag phase with the buccal route and
absorption was more rapid from the intranasal route. CONCLUSIONS:
Intranasal lorazepam has more favourable pharmacokinetics than buccal
lorazepam when considering the need for the rapid blood concentrations
required for seizure termination. Further clinical evaluation of this
route is required.
Armijo, J. A., J. L. Herranz, et al. (2004).
"[Intranasal and buccal midazolam in the treatment of acute seizures]."
Rev Neurol 38(5): 458-68.
AIMS. There are several personal and social problems involved in the administration of rectal diazepam that make it unsuitable for use in public places and by non medical workers, in children and especially in teenagers and adults. Intranasal and oral midazolam could be an alternative to rectal diazepam. We review the efficacy and safety of these ways of administering midazolam, which is already used in some countries as a sedative and as an anticonvulsive drug, despite the fact that it has not yet received authorisation. DEVELOPMENT. Intranasal midazolam (INM) was first used as a sedative in dental extractions, echocardiography, endoscopies or surgery, especially in children. After proving its efficacy electroencephalographically in patients with seizures, it started to be used to interrupt acute seizures. In three randomised trials, the efficacy of intranasal and oral midazolam in hospitalised patients was similar to, and even higher than, that of intravenous or rectal diazepam, with a similar speed of action and safety; no studies have been conducted, however, in the extra hospital milieu and its risk of respiratory depression may be like that of other benzodiazepines. One of the problems of using the parenteral solution for intranasal administration is the irritation that is produced by its acidic pH and the relatively large volume that has to be administered. These problems could be reduced by using aerosols containing a solution of midazolam in cyclodextrin, which accomplishes a greater concentration with a pH that is less acidic. Oral administration can be used in patients with nasal secretions or intense movements of the head. CONCLUSIONS. Intranasal or oral midazolam can improve the treatment of acute seizures in the hospital milieu and, more especially, in the extra hospital milieu when patients are attended by non medical staff. There is a need, however, for trials that prove its efficacy and safety in this situation.
Arya, R., S. Gulati, et al. (2011). "Intranasal versus intravenous lorazepam for control of acute seizures in children: A randomized open-label study." Epilepsia.
Purpose: Intravenous lorazepam is considered the drug of first choice for control of acute convulsive seizures. However, resource or personnel constraints necessitate the study of alternative routes and medications. This study compared the efficacy and adverse effects of intranasal versus intravenous lorazepam in children aged 6-14 years who presented with acute seizures. Methods: This was a randomized open-label study conducted at an Indian hospital from August 2008 to April 2009. One hundred forty-one consecutive children aged 6-14 years who presented convulsing to the emergency room were included. After stabilization, the children were randomized to receive either intravenous or intranasal lorazepam (0.1 mg/kg, maximum 4 mg). The primary outcome measure was clinical seizure remission within 10 min of drug administration. The study was registered with clinicaltrials.gov (NCT00735527). Key Findings: Seventy patients were randomized to receive intravenous and 71 to receive intranasal lorazepam. The patients in the two groups were comparable at baseline. Clinical seizure remission within 10 min of drug administration was found in 80% of the intravenous group as compared to 83.1% of intranasal group. The lower limit of 95% confidence interval for effect size was approximately -9.7%, with an a priori cutoff for noninferiority of -10%. Significance: Intranasal administration of lorazepam is not found to be inferior to intravenous administration for termination of acute convulsive seizures in children.
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.
OBJECTIVE: To compare the
pharmacokinetics, pharmacodynamics, and tolerability of USL261, a
midazolam formulation optimized for intranasal delivery, versus
midazolam intravenous (IV) solution administered intranasally (MDZ-inj
IN) or intravenously (MDZ-inj IV) in healthy adults. METHODS: In this
phase 1, five-way crossover, open-label study, 25 healthy adults (aged
18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg
USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were
collected for 12 h post dose to determine pharmacokinetic profiles.
Pharmacodynamic assessments of sedation and psychomotor impairment also
were conducted. Adverse events, oxygen saturation, and vital signs were
recorded. RESULTS: Increasing USL261 dose corresponded with increases in
midazolam area under the concentration time curve (AUC) and maximum
observed plasma concentration (Cmax ), with all doses demonstrating
rapid median time to Cmax (Tmax ; 10-12 min). USL261 also demonstrated
increased absorption, with a 134% relative bioavailability, compared
with the same MDZ-inj IN dose. USL261 was associated with dose-dependent
increases in sedation and psychomotor impairment (p < 0.05); however,
these effects lasted <4 h and generally did not differ from MDZ-inj IN
or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or
deaths were reported, and no treatment-emergent adverse events (TEAEs)
led to study discontinuation. SIGNIFICANCE: Compared with intranasal
delivery of a midazolam formulation intended for IV delivery, USL261,
optimized for intranasal administration demonstrated improved
bioavailability with similar pharmacodynamic effects. Therefore, USL261
may be a preferable alternative to the currently approved rectal
diazepam treatment for intermittent bouts of increased seizure activity.
Beran, R. G. (2008). "An alternative perspective
on the management of status epilepticus." Epilepsy Behav.
The definition of status epilepticus (SE) has been reduced from 30minutes to 5minutes and this article questions if treatment should not be offered before reaching that window. After provision of first aid, benzodiazepines (BDZ) are the initial form of intervention, with either nasal or buccal midazolam being favored for nonprofessionals. Proper patient supervision, including admission to an intensive care unit for more difficult patients, is endorsed, and the need to warn nonprofessionals of the potential risk of respiratory depression is imperative. The article criticizes the use of phenytoin as the antiepileptic medication (AEM) with which to load patients, as it is no longer a first-line AEM, and argues in favor of using a first-line AEM such as valproate or carbamazepine, or preferably the AEM that previously proved efficacious in a patient with known epilepsy who was noncompliant. Alternative routes of administration of AEMs are discussed, and the use of blood level monitoring, as an adjunct to management, to protect against further episodes of SE, is supported. Touched on in this article are the use of some of the newer AEMs in the management of SE and exploration of treatment strategies that acknowledge that treatment must also include patient education that incorporates techniques to enhance compliance.
Berg, A. K., M. J. Myrvik, et al. (2017). "Pharmacokinetics,
pharmacodynamics, and tolerability of USL261, midazolam nasal spray:
Randomized study in healthy geriatric and non-geriatric adults."
Epilepsy Behav 71(Pt A): 51-59.
AIM: Characterize pharmacokinetics, pharmacodynamics, and
safety/tolerability of USL261 in geriatric adults to inform its
potential for treating bouts of increased seizure activity. METHODS:
Phase 1, randomized, double-blind, 2-way crossover study in healthy
geriatric (>/=65years; n=18) and non-geriatric (18-40years; n=12) adults
evaluated single USL261 doses (2.5 and 5.0mg) administered intranasally.
Pharmacokinetic parameters were estimated for midazolam and
1-hydroxymidazolam (active metabolite), including area under the plasma
concentration-time curve (AUC), maximum plasma concentration (Cmax),
time to Cmax (Tmax), and half-life (t1/2). Stanford Sleepiness Scale and
Observer's Assessment of Alertness/Sedation assessed sedation;
Digit-Symbol Substitution Test assessed psychomotor performance.
RESULTS: Midazolam exposure and plasma concentrations were higher in
geriatric versus non-geriatric adults (geometric mean AUC0-infinity [ng*h/mL]
2.5mg: 70 vs 54, respectively; 5.0mg: 157 vs 110; Cmax [ng/mL] 2.5mg:
27.1 vs 22.5; 5.0mg: 55.8 vs 46.1). USL261 was rapidly absorbed, with no
differences in median Tmax (14.5-17.3min); mean t1/2 was longer in
geriatric subjects. Similar age-related trends were observed for
1-hydroxymidazolam. Mean maximum observed pharmacodynamic effects were
not significantly different between age groups, though were more
pronounced following 5.0 versus 2.5mg (P<.05); return to baseline was
generally achieved within 4h. USL261 was generally well tolerated, with
similar adverse event rates between age groups. CONCLUSIONS: Despite
increased midazolam exposure in geriatric subjects, there were no
differences between age groups in pharmacodynamic effects or adverse
event rates. USL261 was rapidly absorbed and pharmacodynamic effects
returned to baseline within ~4h, regardless of age. Dose-dependent
pharmacokinetic and maximum pharmacodynamic effects were observed.
Overall, pharmacokinetic findings for USL261 were similar to studies
evaluating intravenous midazolam, whereas pharmacodynamic effects were
less pronounced in the elderly than previously reported.
Bhattacharyya, Kalra, et al. (2006). "Intranasal
midazolam vs rectal diazepam in acute childhood seizures." Pediatr
Neurol 34(5): 355-9.
One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.
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.
BACKGROUND: Prompt treatment of status epilepticus (SE) is
associated with better outcomes. Rectal diazepam (DZP) and
nonintravenous (non-IV) midazolam (MDZ) are often used in the treatment
of early SE instead of intravenous applications. The aim of this review
was to determine if nonintravenous MDZ is as effective and safe as
intravenous or rectal DZP in terminating early SE seizures in children
and adults. METHODS: We searched the Cochrane Central Register of
Controlled Trials (CENTRAL), ClinicalTrials.gov, and MEDLINE for
randomized controlled trials comparing non-IV MDZ with DZP (by any
route) in patients (all ages) with early SE defined either as seizures
lasting >5min or as seizures at arrival in the emergency department. The
following outcomes were assessed: clinical seizure cessation within
15min of drug administration, serious adverse effects, time interval to
drug administration, and time from arrival in the emergency department
to seizure cessation. Outcomes were assessed using a random-effects
Mantel-Haenszel meta-analysis to calculate risk ratio (RR), odds ratio
(OR) and mean difference with 95% confidence intervals (95% CIs).
RESULTS: Nineteen studies with 1933 seizures in 1602 patients (some
trials included patients with more than one seizure) were included. One
thousand five hundred seventy-three patients were younger than 16years.
For seizure cessation, non-IV MDZ was as effective as DZP (any route)
(1933 seizures; RR: 1.03; 95% CIs: 0.98 to 1.08). No difference in
adverse effects was found between non-IM MDZ and DZP by any route (1933
seizures; RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between
arrival and seizure cessation was significantly shorter with non-IV MDZ
by any route than with DZP by any route (338 seizures; mean difference:
-3.67min; 95% CIs: -5.98 to -1.36); a similar result was found for time
from arrival to drug administration (348 seizures; mean difference:
-3.56min; 95% CIs: -5.00 to -2.11). A minimal difference was found for
time interval from drug administration to clinical seizure cessation,
which was shorter for DZP by any route than for non-IV MDZ by any route
(812 seizures; mean difference: 0.56min; 95% CIs: 0.15 to 0.98min). Not
all studies reported information on time intervals. Comparison by each
way of administration failed to find a significant difference in terms
of clinical seizure cessation and occurrence of adverse effects. The
only exception was the comparison between buccal MDZ and rectal DZP,
where MDZ was more effective than rectal DZP in terminating SE but only
when results were expressed as OR (769 seizures; OR: 1.78; 95% CIs: 1.11
to 2.85; RR: 1.15; 95% CIs: 0.85 to 1.54). Only one study was entirely
conducted in an adult population (21 patients, aged 31 to 69years),
showing no difference in efficacy or time to seizure cessation after
drug administration between intranasal MDZ and rectal DZP. CONCLUSIONS:
Non-IV MDZ is as effective and safe as intravenous or rectal DZP in
terminating early SE in children and probably also in adults. Times from
arrival in the emergency department to drug administration and to
seizure cessation are shorter with non-IV MDZ than with intravenous or
rectal DZP, but this does not necessarily result in higher seizure
control. An exception may be the buccal MDZ, which, besides being
socially more acceptable and easier to administer, might also have a
higher efficacy than rectal DZP in seizure control. This article is part
of a Special Issue entitled Status Epilepticus.
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.
Crawford, D. (2016). "Implementation of Intranasal Midazolam
for Prolonged Seizures in a Child Neurology Practice." J Neurosci
Nurs.
Currently, evidence supports the use of intranasal midazolam as an
effective, and in many cases, preferable treatment option for prolonged
seizures in children. Despite this knowledge, intranasal midazolam is
not routinely found as a standard of care. The goal of this project was
to implement the use of intranasal midazolam as a rescue medication for
prolonged seizures within a child neurology practice and, in doing so,
create a model for implementation that would be replicable for other
practice sites. This project focused on the development of a process to
make intranasal midazolam available as a treatment option and then the
creation of an educational intervention for providers within a child
neurology practice. Provider surveys analyzed provider attitudes toward
intranasal midazolam and its frequency of use. Because of this project,
a dramatic increase in the prescribing of intranasal midazolam was
observed within a child neurology practice.
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)
In convulsive status epilepticus (SE), achieving seizure control within the first 1-2hours after onset is a significant determinant of outcome. Treatment is also more likely to work and be cost effective the earlier it is given. Initial first aid measures should be accompanied by establishing intravenous access if possible and administering thiamine and glucose if required. Calling for help will support efficient management, and also the potential for video-recording the events. This can be done as a best interests investigation to inform later management, provided adequate steps to protect data are taken. There is high quality evidence supporting the use of benzodiazepines for initial treatment. Midazolam (buccal, intranasal or intramuscular) has the most evidence where there is no intravenous access, with the practical advantages of administration outweighing the slightly slower onset of action. Either lorazepam or diazepam are suitable IV agents. Speed of administration and adequate initial dosing are probably more important than choice of drug. Although only phenytoin (and its prodrug fosphenytoin) and phenobarbitone are licensed for established SE, a now considerable body of evidence and international consensus supports the utility of both levetiracetam and valproate as options in established status. Both also have the advantage of being well tolerated as maintenance treatment, and possibly a lower risk of serious adverse events. Two adequately powered randomized open studies in children have recently reported, supporting the use of levetiracetam as an alterantive to phenytoin. The results of a large double blind study also including valproate are also imminent, and together likely to change practice in benzodiazepine-resistant SE.
de Haan, G. J., P. van der Geest, et al. (2010). "A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations." Epilepsia 51(3): 478-482.
Rectal diazepam is established as a standard rescue or emergency treatment for seizure or status epilepticus; however, the rectal route of administration has not been universally accepted. To determine if an alternative route of administration of a benzodiazepine was equally effective, we compared a novel midazolam HCl concentrated nasal spray (MDZ-n) with diazepam rectal solution (DZP-r) in the treatment of prolonged seizures in a residential epilepsy center. In 21 adult patients with medically refractory epilepsy, 124 seizure-exacerbations were treated by their caregivers, alternatively with 10 mg DZP-r and 10 mg concentrated MDZ-n, two or three treatments with each medication for each patient. No difference was demonstrated in efficacy or time to effect between the two drugs. Common treatment emerging adverse effects were drowsiness for both drugs in more than 50% of the administrations, and short-lasting local irritation after 29% of MDZ-n. No severe adverse events occurred. The nasal spray was preferred to the rectal solution by 16 of 21 caregivers and patients conjointly. MDZ-n was equal to DZP-r with respect to efficacy and side effects in the suppression of seizure exacerbations. The majority of patients and caregivers preferred the nasal spray over the rectal formulation.
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.
OBJECTIVE: To evaluate the safety and efficacy of a novel formulation of
midazolam administered as a single-dose nasal spray (MDZ-NS) in the
outpatient treatment of patients experiencing seizure clusters (SCs).
METHODS: This was a phase III, randomized, double-blind,
placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients
age >/=12 years on a stable regimen of antiepileptic drugs. Following an
in-clinic test dose phase (TDP), patients entered an outpatient
comparative phase (CP) and were randomized (2:1) to receive double-blind
MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they
experienced an SC. The primary efficacy end point was treatment success
(seizure termination within 10 minutes and no recurrence 10 minutes to 6
hours after trial drug administration). Secondary efficacy end points
were proportion of patients with seizure recurrence 10 minutes to 4
hours, and time-to-next seizure >10 minutes after double-blind drug
administration. Safety was monitored throughout. RESULTS: Of 292
patients administered a test dose, 262 patients were randomized, and 201
received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67
placebo, modified intent-to-treat population). A significantly greater
proportion of MDZ-NS- than placebo-treated patients achieved treatment
success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ-NS- than
placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%;
P = 0.0043). Time-to-next seizure analysis showed early separation
(within 30 minutes) between MDZ-NS and placebo that was maintained
throughout the 24-hour observation period (21% difference at 24 hours; P
= 0.0124). Sixteen patients (5.5%) discontinued because of a
treatment-emergent adverse event (TEAE) during the TDP and none during
the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and
placebo groups, respectively, experienced >/=1 TEAE. SIGNIFICANCE:
MDZ-NS was superior to placebo in providing rapid, sustained seizure
control when administered to patients experiencing an SC in the
outpatient setting and was associated with a favorable safety profile.
Fisgin, T., Y. Gurer, et al. (2000). "Nasal
midazolam effects on childhood acute seizures." J Child Neurol
15(12): 833-5.
Sixteen children, aged from 2 months to 14 years, with a diagnosis of acute seizures and seen at Dr. Sami Ulus Child Health and Disease Center, were included in this study. Midazolam (5 mg/mL) 0.2 mg/kg was administered intranasally in 30 seconds by an injector. The heart rate, respiratory rate, blood pressure, and oxygen saturation were recorded at 0, 5, and 10 minutes after administration. The seizures of three (18.7%) patients terminated within 1 minute, of seven (43.7%) patients in 1 to 2 minutes, and of three (18.7%) patients in 2 to 5 minutes. However, three (18.7%) patients did not respond to treatment. As a result, it was concluded that intranasal midazolam administration is easy and effective. The half-life of midazolam is shorter than diazepam, and midazolam has fewer complications when compared with diazepam. It is easier to use in nasal drop and spray forms.
Fisgin, T., Y. Gurer, et al. (2002). "Effects of
intranasal midazolam and rectal diazepam on acute convulsions in
children: prospective randomized study." J Child Neurol 17(2):
123-6.
In this study, the effects and side effects of rectal diazepam and intranasal midazolam were compared in the treatment of acute convulsions in children to develop a practical and safe treatment protocol. In the diazepam group, the seizures of 13 (60%) patients terminated in 10 minutes; however, 9 (40%) patients did not respond. In the midazolam group, 20 (87%) patients responded in 10 minutes, but 3 (13%) patients did not respond. Regarding the anticonvulsant effect, midazolam was found to be more effective than diazepam, and the difference was statistically significant (P < .05). The necessity of a second drug for the seizures that did not stop with the first drug was higher in the diazepam group than the midazolam group, and the difference was statistically significant (P < .05). We conclude that as an antiepileptic agent, intranasal midazolam is more effective than rectal diazepam. After administration, we did not observe any serious complications. Further investigations are necessary; however, intranasal administration is easy, so if the nasal drop and spray forms used in some European countries and the United States are available worldwide, it will be very useful for physicians in the emergency room.
Fujita, H., H. Muranaka, et al. (2001).
"[Intranasal midazolam for prevention of status epilepticus]." No To
Hattatsu 33(3): 283-4.
Gilat, Kadar, et al. (2005). "Anticonvulsant
treatment of sarin-induced seizures with nasal midazolam: an
electrographic, behavioral, and histological study in freely moving
rats." Toxicol Appl Pharmacol 209(1): 74-85.
Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 +/- 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 +/- 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.
Gilat, E., M. Goldman, et al. (2003). "Nasal
midazolam as a novel anticonvulsive treatment against
organophosphate-induced seizure activity in the guinea pig." Arch
Toxicol 77(3): 167-72.
Seizures and status epilepticus, which may contribute to brain injury, are common consequences of exposure to organophosphorus (OP) cholinesterase inhibitors. Effective management of these seizures is critical. To investigate the efficacy of nasal midazolam as an anticonvulsive treatment for OP exposure, as compared to intramuscular midazolam, guinea pigs were connected to a recording swivel for electrocorticograph (ECoG) monitoring and clinical observation. The experimental paradigm consisted of pyridostigmine pretreatment (0.1 mg/kg i.m.) 20 min prior to sarin exposure (1.2x LD(50,) 56 micro g/kg i.m.). One minute post-exposure, atropine (3 mg/kg i.m.) and TMB-4 (1 mg/kg im) were administered. Within 3-8 min after sarin exposure all animals developed electrographic seizure activity (EGSA), with convulsive behavior. Treatment with midazolam (1 mg/kg i.m.) 10 min after the onset of EGSA abolished EGSA within 389+/-181 s. The same dose was not effective, in most cases, when given 30 min after onset. However, a higher dose (2 mg/kg) was found efficacious after 30 min (949+/-466 s). In contrast, nasal application of midazolam (1 mg/kg) was found most effective, with significant advantages, in amelioration of EGSA and convulsive behavior, when given 10 min (216+/-185 s) or 30 min (308+/-122 s) following the onset of EGSA ( P<0.001). Thus, nasal midazolam could be used as a novel, rapid and convenient route of application against seizure activity induced by nerve agent poisoning.
Gizurarson, S., F. K. Gudbrandsson, et al.
(1999). "Intranasal administration of diazepam aiming at the treatment
of acute seizures: clinical trials in healthy volunteers." Biol Pharm
Bull 22(4): 425-7.
Intranasal administration of diazepam may be a practical alternative to the conventional acute medication of seizures, such as status epilepticus. Nine healthy students participated in an open crossover study on intranasal versus intravenous administration of diazepam (2 mg). Blood samples were collected, pharmacodynamic tests were performed, and the volunteers filled out questionnaire. Peak concentration was achieved after 18+/-11 min and the bioavailability was 50.4+/-23.3%. A pharmacodynamic effect was observed after about 5 min, but the dose, even for i.v. administration, was too low to generate a strong measurable effect. The results indicate that intranasally administered diazepam may be an effective alternative to i.v. administration in relief of seizures, e.g. in an acute situation when a physician or nurse is not available on location.
Goyal and Wiznitzer (2006). "Emergency
management of seizures in children." Lancet 367(9522): 1555-6.
Harbord, M. G., N. E. Kyrkou, et al. (2004).
"Use of intranasal midazolam to treat acute seizures in paediatric
community settings." J Paediatr Child Health 40(9-10): 556-8.
OBJECTIVES: To evaluate the acceptability of intranasal midazolam (INM) in acute seizure management in the community. METHODS: Parents and staff in residential and educational settings were trained in first aid and seizure management and the administration of INM. Feedback was obtained from those who had given INM over the 30-month period September 2000-March 2003. RESULTS: Intranasal midazolam was administered to 22 children for a total of 54 seizures (range 1-6 seizures each). The dose was 0.2-0.3 mg/kg rounded down to 1 or 2 of the 5 mg in 1-mL plastic ampoules, with the anticonvulsant instilled into the child's nose directly from the plastic ampoule. Seizures were effectively stopped on 48 occasions, i.e. 89%, while no respiratory arrests occurred. Thirty carers had given INM to a convulsing child and 27 (90%) reported no difficulty in administering it. Fifteen people had also previously administered rectal diazepam and INM was considered easier to administer than rectal diazepam by 13 while a preference to use INM rather than rectal diazepam was indicated by 14. CONCLUSION: This study has shown that INM is an acceptable treatment option as a first aid response for acute seizures. We believe that INM should be considered as the preferred alternative in the community setting, as it is easier to administer and is more dignified for the patient than rectal diazepam.
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.
The pharmacokinetics and pharmacodynamics of a highly
concentrated cyclodextrin-based intranasal (i.n.) midazolam formulation
containing the absorption-enhancer chitosan were studied in 12 healthy
volunteers and compared with intravenous (i.v.) midazolam. The
pharmacodynamic (PD) effects were assessed using quantitative
electroencephalography (EEG). Maximal plasma concentrations of 63 and
110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n.
midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam,
the times to onset of significant EEG effects in the beta2 band (18-25
Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of
response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively.
A sigmoid maximum-effect (E(max)) model indicated disequilibrium between
plasma and effect-site concentrations, with equilibration half-lives of
2.1-4.8 min. The observed pharmacokinetic-PD (PK-PD) properties suggest
that i.n. midazolam deserves to be evaluated as an easy and noninvasive
method of administering a first benzodiazepine dose, e.g., in
out-of-hospital emergency settings with no immediate i.v. access.
Harnden, A. (2001). "Intranasal midazolam for
treating febrile seizures in children. Caution is required in applying
hospital based evidence to primary care population." Bmj
322(7278): 108.
Haut, S. R., S. Seinfeld, et al. (2016). "Benzodiazepine use
in seizure emergencies: A systematic review." Epilepsy Behav 63:
109-117.
PURPOSE: The aim of this review was to systematically examine safety and
efficacy outcomes, as well as patient/caregiver satisfaction, from
clinical studies in pediatric and adult patients treated with
benzodiazepines (BZDs) through various administration routes in response
to seizure emergencies. METHODS: A literature search was conducted to
identify articles describing the use of various routes of administration
(RoAs) of BZDs for the treatment of seizure emergencies through April
21, 2015, using Embase and PubMed(R). Eligible studies included (a)
randomized controlled trials or (b) controlled nonrandomized clinical
trials, either retrospective or prospective. Outcome assessments
reviewed were 1) time to administration, 2) time to seizure termination,
3) rate of treatment failure, 4) prevention of seizure recurrence, 5)
patient and caregiver treatment satisfaction, 6) adverse events related
to BDZ treatment or RoA, and 7) respiratory adverse events. RESULTS:
Seventy-five studies evaluated safety and efficacy using individual or
comparator BDZs of various RoAs for treating seizure emergencies in
all-aged patients with epilepsy. Buccal, intranasal (IN), or
intramuscular (IM) BZDs were often more rapidly administered compared
with rectal and intravenous (IV) formulations. Time to seizure
termination, seizure recurrence rates, and adverse events were generally
similar among RoAs, whereas nonrectal RoAs resulted in greater patient
and caregiver satisfaction compared with rectal RoA. SIGNIFICANCE:
Results of this systematic literature review suggest that nonrectal and
non-IV BZD formulations provide equal or improved efficacy and safety
outcomes compared with rectal and IV formulations for the treatment of
seizure emergencies.
Henney, H. R., 3rd, M. R. Sperling, et al. (2014). "Assessment of
pharmacokinetics and tolerability of intranasal diazepam relative to
rectal gel in healthy adults." Epilepsy Res
108(7): 1204-1211.
Diazepam rectal gel (RG) is currently the only approved rescue therapy
for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue
therapy for seizure clusters that is effective, and more convenient to
administer with a socially acceptable method of delivery. An intranasal
diazepam formulation has been developed, and this study evaluates the
tolerability and bioavailability of diazepam nasal spray (NS) relative
to an equivalent dose of diazepam-RG in healthy adults. Twenty-four
healthy adults were enrolled in a phase 1, open-label, 3-period
crossover study. Plasma diazepam and metabolite concentrations were
measured by serial sampling. Dose proportionality for 5- and 20-mg
intranasal doses and the bioavailability of 20mg diazepam-NS relative to
20mg diazepam-RG were assessed by maximum plasma concentration (Cmax)
and systemic exposure parameters (AUC0-infinity and AUC0-24). The mean
Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 +/- 106
and 328 +/- 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects
administered intranasal and rectal gel formulations experienced nasal
and rectal leakage, respectively. Diazepam absorption following
intranasal administration was consistent but 3 subjects with diazepam-RG
had low plasma drug levels at the earliest assessment of 5 min, due to
poor retention, and were excluded from analysis. Excluding them, the
treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence
intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89
(0.80-0.98), respectively, suggesting that the bioavailability was
comparable between the two formulations. Dose proportionality was
observed between the lowest and highest dose-strengths of intranasal
formulation. Both intranasal and rectal treatments were well tolerated
with mild to moderate adverse events. Results suggest that a single-dose
of 20mg diazepam-NS is tolerable and comparable in bioavailability to
that of diazepam-RG. The intranasal formulation may provide caregivers
and patients with a more socially acceptable and convenient alternative
rescue therapy in the acute treatment of seizure clusters.
Hirsch, L.J., Intramuscular
versus intravenous benzodiazepines for prehospital treatment of status
epilepticus. N Engl J Med, 2012.
366(7): p. 659-60.
Holsti, M., B. L. Sill, et al. (2007).
"Prehospital intranasal midazolam for the treatment of pediatric
seizures." Pediatr Emerg Care 23(3): 148-53.
BACKGROUND: The local emergency medical services (EMS) council implemented a new pediatric treatment protocol using a Mucosal Atomization Device (MAD) to deliver intranasal (IN) midazolam for seizure activity. METHODS: We sought to compare outcomes in seizing pediatric patients treated with IN midazolam using a MAD (IN-MAD midazolam) to those treated with rectal (PR) diazepam, 18 months before and after the implementation of the protocol. RESULTS: Of 857 seizure patients brought by EMS to our emergency department (ED), 124 patients (14%) had seizure activity in the presence of EMS and were eligible for inclusion in this study. Of the 124 patients eligible for this study, 67 patients (54%) received no medications in the prehospital setting, 39 patients (32%) were treated with IN-MAD midazolam, and 18 patients (15%) were treated with PR diazepam. Median seizure time noted by EMS was 19 minutes longer for PR diazepam (30 minutes) when compared with IN-MAD midazolam (11 minutes, P = 0.003). Patients treated with PR diazepam in the prehospital setting were significantly more likely to have a seizure in the ED (odds ratio [OR], 8.4; confidence interval [CI], 1.6-43.7), ED intubation (OR, 12.2; CI, 2.0-75.4), seizure medications in the ED to treat ongoing seizure activity (OR, 12.1; CI, 2.2-67.8), admission to the hospital (OR, 29.3; CI, 3.0-288.6), and admission to the pediatric intensive care unit (OR, 53.5; CI, 2.7-1046.8). CONCLUSIONS: The IN-MAD midazolam controlled seizures better than PR diazepam in the prehospital setting and resulted in fewer respiratory complications and fewer admissions.
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.
Objective: To compare intranasal midazolam using a Mucosal Atomization Device (IN-MMAD) with rectal diazepam (RD) for the home treatment of seizures in children with epilepsy.Methods: 358 pediatric epilepsy subjects were prospectively enrolled from July 2006 through September 2008. Caretakers were randomized to use either 0.2 mg/kg of IN- child’s next seizure lasting longer than five minutes. Outcome data were summarized using medians and interquartile ranges (IQR) in minutes. Results: 92 caretakers administered a study medication to their child during a seizure (50 IN-MMAD, 42 RD). Groups were similar with regard to age, gender, daily anti-epileptic medications, and caretakers’ past experience with RD. Median IQR for seizure time before medication administration was IN-MMAD: 6.0 (4.8, 10.0) and RD: 6.0 (5.0, 10.0), time from drug administration to seizure cessation was IN-MMAD: 3.0 (1.0, 10.1) and RD: 4.3 (2.0, 14.5), and total seizure time was IN-MMAD: 12.0 (7.0, 21.0) and RD: 14.3 (7.5, 30.0). No differences were found between treatment groups with regard to repeat/prolonged seizures, need for emergency services, respiratory depression, emergency room visits, or hospitalization. Using a ten-point scale, caretakers report that IN-MMAD was easier to administer (9.2, CI: 8.9, 9.6 vs. 8.0, CI: 7.2, 8.7). Overall satisfaction with medication was higher in the IN-MMADÒ group (8.3, CI: 7.6, 9.0 vs. 7.2, CI: 6.4, 8.0).Conclusions: IN-MMAD was as effective as RD, as a “rescue medication” in terminating seizures at home in pediatric epilepsy patients. Ease of administration and overall satisfaction were higher with IN-MMAD compared to RD.
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.
Seizures in the pediatric population commonly occur, and when proper rescue medication is not administered quickly, the risk of neurologic compromise emerges. For many years, rectal diazepam has been the standard of care, but recent interest in a more cost-effective, safe alternative has led to the investigation of intranasal midazolam for this indication. Although midazolam and diazepam are both members of the benzodiazepine class, the kinetic properties of these 2 anticonvulsants vary. This paper will review available data pertaining to the efficacy, safety, cost, and pharmacokinetics of intranasal midazolam versus rectal diazepam as treatment for acute seizures for children in the prehospital, home, and emergency department settings.
Full article link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668946/
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.
Administering diazepam intravenously or rectally in an adult with
status epilepticus can be difficult and time consuming. The aim of this
study was to examine whether intranasal diazepam is an effective
alternative to intravenous diazepam when treating status epilepticus. We
undertook a retrospective cohort study based on the medical records of
19 stroke patients presenting with status epilepticus to our
institution. We measured the time between arrival at the hospital, the
intravenous or intranasal administration of diazepam, and the seizure
termination. Intranasal diazepam was administered about 9 times faster
than intravenous diazepam (1 vs 9.5 minutes, P = 0.001), resulting in
about 3-fold reduction in the time to termination of seizure activity
after arrival at the hospital (3 minutes compared with 9.5 minutes in
the intravenous group, P = 0.030). No adverse effects of intranasal
diazepam were evident from the medical records. Intranasal diazepam
administration is safer, easier, and quicker than intravenous
administration.
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.
Objective:
Acute seizure
attack is
a stressful
experience both
for health
care personnel
and parents.
These attacks might
cause morbidity
and mortality
among patients,
so reliable
methods to
control the
seizure preferably at home should be developed. This study was
performed to measure the time needed to control seizure attacks using
intranasal midazolam compared to the common treatment (intravenous
diazepam) and to evaluate its probable side effects. Methods:
This study
was conducted
as a
not blind
randomized clinical
trial among
60 patients
coming to Imam
Ali Hospital,
Zahedan, Iran.
The patients
were 2
months to
15 years
old children
coming to
our emergency department suffering from an acute seizure episode.
Intranasal midazolam was administered 0.2 mg/kg equally dropped in both
nostrils for case group and intravenous diazepam was administered
0.3mg/kg via IV line for control group. After both treatments the time
needed to control the seizure was registered by the
practitioner. Pulse
rate and
O
saturation were
recorded at
patients’ entrance
and in minutes
5 and 10 after drug
administration. Findings: The time needed to control seizure using
intranasal midazolam (3.16±1.24) was statistically shorter than
intravenous diazepam
(6.42±2.59) if
the time
needed to
establish IV
line in
patients treated
by intravenous diazepam is taken into account (P<0.001). The
readings for O
saturation or heart rate did not
indicate a
statistically
significant difference
between two
groups of
patients either
at entrance
or 5
and 10 minutes after
drug administration. Conclusion:
Considering the shorter time needed to control acute seizure
episodes compared to intravenous diazepam and its safety record,
intranasal midazolam seems to be a good candidate to replace diazepam,
as the drug of choice, in controlling this condition.
Jeannet, P. Y., E. Roulet, et al. (1999). "Home
and hospital treatment of acute seizures in children with nasal
midazolam." Eur J Paediatr Neurol 3(2): 73-7.
Rectal diazepam is widely used in the treatment of acute seizures in children but has some disadvantages. Nasal/sublingual midazolam administration has been recently investigated for this purpose but never at home or in a general paediatric hospital. The aim of this open study was to determine the efficacy, the tolerance and the applicability of nasal midazolam during acute seizures in children both in hospital and at home. We included known epileptic children for treatment at home and all children with acute seizures in the hospital. In all, 26 children were enrolled, 11 at home and 17 in the hospital (including two treated in both locations); only one had simple febrile seizure. They had a total of 125 seizures; 122 seizures (98%) stopped within 10 minutes (average 3.6 minutes). Two patients in the hospital did not respond and in three, seizures recurred within 3 hours. None had serious adverse effects. Parents had no difficulties administering the drug at home. Most of those who were using rectal diazepam found that nasal midazolam was easier to use and that postictal recovery was faster. Among 15 children who received the drug under electroencephalogram monitoring (six without clinical seizures), the paroxysmal activity disappeared in ten and decreased in three. Nasal midazolam is efficient in the treatment of acute seizures. It appears to be safe and most useful outside the hospital in severe epilepsies, particularly in older children because it is easy for parents to use. These data should be confirmed in a larger sample of children. Its usefulness in febrile convulsions also remains to be evaluated.
Johnson, T. (2001). "Intranasal midazolam for
treating febrile seizures in children. Caution is advised in
interpreting trial conclusions." Bmj 322(7278): 107.
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.
OBJECTIVE: To evaluate the tolerability and efficacy of the ictal
and immediate postictal application of intranasal midazolam (in-MDZ) in
adolescents and adults during video-electroencephalography (EEG)
monitoring. METHODS: Medical records of all patients treated with in-MDZ
between 2008 and 2014 were reviewed retrospectively. For each single
patient, the time span until recurrence of seizures was analyzed after
an index seizure with and without in-MDZ application. To prevent
potential bias, we defined the first seizure with application of in-MDZ
as the in-MDZ index seizure. The control index seizure was the
preceding, alternatively the next successive seizure without application
of in-MDZ. RESULTS: In total, 75 epilepsy patients (mean age 34 +/- 14.7
years; 42 male, 33 female) were treated with in-MDZ (mean dose 5.1 mg).
Adverse events were observed in four patients (5.3%), and no serious
adverse events occurred. The median time after EEG seizure onset before
administration of in-MDZ was 2.17 min (interquartile range [IQR] 03.82;
range 0.13-15.0 min). Over the next 12 h after in-MDZ, the number of
seizures was significantly lower (p = 0.031). The median seizure-free
interval was significantly longer following treatment with in-MDZ (5.83
h; IQR 6.83, range 0.4-23.87) than it was for those with no in-MDZ
treatment (2.37 h; IQR 4.87, range 0.03-21.87; p = 0.015). Conversely,
the likelihood of the patient developing a subsequent seizure was four
times higher (odds ratio [OR] 4.33, 95% confidence interval [CI]
1.30-14.47) in the first hour and decreased gradually after 12 h (OR
1.5, 95% CI 1.06-2.12). The occurrence of generalized tonic-clonic
seizures was lower in the in-MDZ group in the 24-h observation period
(OR 4.67, 95% CI 1.41-15.45; p = 0.009). SIGNIFICANCE: Ictal and
immediate postictal administration of in-MDZ was well tolerated and not
associated with serious adverse events. We demonstrated a significant
reduction of subsequent seizures (all seizure types) for a 12 h period
and of generalized tonic-clonic seizures for 24 h following in-MDZ.
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.
OBJECTIVE: We sought to evaluate the efficacy and tolerability of
intranasal midazolam (in-MDZ) as first-line inhospital therapy in
patients with status epilepticus (SE) during continuous EEG recording.
METHODS: Data on medical history, etiology and semiology of SE,
anticonvulsive medication usage, efficacy and safety of in-MDZ were
retrospectively reviewed between 2015 and 2018. Time to end of SE
regarding the administration of in-MDZ and ss-band effects were analyzed
on EEG and with frequency analysis. RESULTS: In total, 42 patients (mean
age: 52.7 +/- 22.7 years; 23 females) were treated with a median dose of
5 mg of in-MDZ (range: 2.5-15 mg, mean: 6.4 mg, SD: 2.6) for SE. The
majority of the patients suffered from nonconvulsive SE (n = 24; 55.8%).
In total, 24 (57.1%) patients were responders, as SE stopped following
the administration of in-MDZ without any other drugs being given. On
average, SE ceased on EEG at 05:05 (minutes:seconds) after the
application of in-MDZ (median: 04:56; range: 00:29-14:53; SD:03:13).
Frequency analysis showed an increased ss-band on EEG after the
application of in-MDZ at 04:07 on average (median: 03:50; range:
02:20-05:40; SD: 01:09). Adverse events were recorded in six patients
(14.3%), with nasal irritations present in five (11.9%) and prolonged
sedation occurring in one (2.6%) patient. CONCLUSIONS: This pharmaco-EEG-based
study showed that in-MDZ is effective and well-tolerated for the acute
treatment of SE. EEG and clinical effects of in-MDZ administration
occurred within 04:07 and 5:05 on average. Intranasal midazolam appears
to be an easily applicable and rapidly effective alternative to buccal
or intramuscular application as first-line treatment if an intravenous
route is not available.
Kendall, J. L., M. Reynolds, et al. (1997).
"Intranasal midazolam in patients with status epilepticus." Ann Emerg
Med 29(3): 415-7.
The patient in status epilepticus presents many challenges to the emergency physician. IV access is frequently difficult to achieve, and prolonged attempts at access can jeopardize the patient and endanger the caregiver. We present two cases in which the administration of intranasal midazolam appeared to successfully terminate status epilepticus. No adverse effects were noted. Studies are needed to clarify the safety, optimal dosing, and clinical utility of this treatment modality.
Koekkoek, J. A., M. S. Boddaert, et al. (2014). "[Gliomas: fighting
until the end against epilepsy; administration of antiepileptic drugs in
the end-of-life phase]." Ned Tijdschr Geneeskd
158(1): A6924.
In patients with high-grade glioma seizures occur relatively frequently
during the end-of-life phase. At some point, the use of oral
anti-epileptic drugs is no longer possible due to swallowing
difficulties caused by advanced tumour progression. We have established
a draft guideline and propose that anti-epileptic drugs be prescribed by
alternative routes of administration in the end-of-life phase in glioma
patients with known epilepsy who develop swallowing difficulties. Buccal
clonazepam would be our drug of first choice as a maintenance treatment
in addition to intranasal midazolam for the acute management of
seizures. Adequate treatment of epileptic seizures, particularly during
the end-of-life phase, can help to maintain quality of life as long as
possible in patients with high-grade glioma.
Koren, G. (2000). "Intranasal midazolam for
febrile seizures. A step forward in treating a common and distressing
condition." Bmj 321(7253): 64-5.
Kutlu, N. O., M. Dogrul, et al. (2003). "Buccal
midazolam for treatment of prolonged seizures in children." Brain Dev
25(4): 275-8.
Midazolam is a relatively new anticonvulsive agent in the benzodiazepine group. It has a short onset of duration and is practical for use, providing several alternatives such as intravenous, intramuscular, and intranasal routes. The buccal route could be an alternative choice for seizure control in an emergency setting. However, no sufficient reports are available on buccal midazolam administration. The present study was designated to examine the efficacy of buccal midazolam in children at different ages with seizures of more than 5 min duration. Nineteen previously unreported children, aged from 1 month to 15 years, were treated with a 0.3 mg/kg dose of buccal midazolam; 13 had prolonged seizures, and six had status epilepticus, with a duration of 5-45 min (mean 22 min). Sixteen of 19 seizures (84.2%) stopped within 10 min of buccal midazolam being given. The drug efficacy in patients with status epilepticus was 50%. However, all patients with convulsions shorter than 30 min showed a perfect response (100%). Convulsion episodes stopped within 3.89+/-2.22 min (median time 3 min). Seizure duration was correlated with cessation of seizure (r=0.76, P<0.001). No clinically important side effects were seen in any patient. On the basis of this experience, we concluded that a 0.3 mg/kg dose of buccal administration of midazolam might offer an effective treatment in all ages of children.
Kutlu, N. O., C. Yakinci, et al. (2000).
"Intranasal midazolam for prolonged convulsive seizures." Brain Dev
22(6): 359-61.
In order to determine the efficiency of intranasal midazolam in prolonged convulsive episodes, we conducted a prospective study in children with various types of seizures. Nine patients (six boys, three girls; age range 6 months to 9 years) with prolonged convulsions lasting more than 10 min were treated with intranasal midazolam, 0.3 mg/kg. The success rate was 100% with only one case requiring a second dose. Estimated duration of seizures was 12-30 min (mean 18.6) while mean time elapsed until cessation of seizures was 139.6 s (range 60-480). No significant adverse effects were noted except for one patient who had seizures secondary to serious CNS infection and respiratory depression after intranasal midazolam.
Kyrkou, Harbord, et al. (2006). "Community use
of intranasal midazolam for managing prolonged seizures." J Intellect
Dev Disabil 31(3): 131-8.
Background Until a few years ago, rectal diazepam (RD) was the only option available to parents and carers managing prolonged seizures. However, its use in the community was limited due to the requirement for privacy, and because education staff in South Australia are not permitted to carry out invasive procedures.Method Following a literature review, a seizure management training package was developed to enhance the implementation of a trial treatment protocol for the administration of intranasal midazolam (INM). Parents, carers and education staff were later surveyed about their experiences and perceptions.Results Intranasal midazolam was administered to 131 people (51 children and 80 adults), with 96.9% control of seizures, and only one minor adverse event. Parents expressed a preference for INM over RD because of the shorter time it took to take effect and wear off, and the ability to administer it in public if necessary.Conclusion Intranasal midazolam is a safe and practical alternative to rectal diazepam for managing prolonged seizures in the community.
Lagae, L. (2014). "Overview of clinical efficacy and risk data of
benzodiazepines for prolonged seizures." Epileptic Disord
16 Suppl 1: 44-49.
An historical overview is provided regarding the use
of benzodiazepines for the treatment of acute prolonged convulsive
seizures. It is clear that intravenous benzodiazepines remain a first
step for the in-hospital treatment of prolonged seizures or status
epilepticus. However, in the community, in a pre-hospital situation,
intravenous administration is not possible. In recent years, it was
shown that rectal, buccal, intranasal, and intramuscular administration
of benzodiazepines is very effective as a first and safe treatment step.
In many cases, rectal diazepam is not socially acceptable anymore, and
therefore more emphasis is now put on buccal, intranasal, and
intramuscular administration.
At present, based on the available data, midazolam is the product of
choice for the acute treatment of prolonged convulsive seizures.
Lahat, E., M. Goldman, et al. (2000).
"Comparison of intranasal midazolam with intravenous diazepam for
treating febrile seizures in children: prospective randomised study."
Bmj 321(7253): 83-6.
Objective: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design: Prospective randomised study. Setting: Paediatric emergency department in a general hospital. Subjects: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures: Time from arrival at hospital to starting treatment and cessation of seizures. Results: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7. 9 to 8.3). No significant side effects were observed in either group. Conclusion: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.
Lahat, E., M. Goldman, et al. (1998).
"Intranasal midazolam for childhood seizures." Lancet 352(9128):
620.
Lahat, E., M. Goldman, et al. (1998).
"Intranasal midazolam for childhood seizures [letter]." Lancet
352(9128): 620.
Lissauer, S., J. Kenny, et al. (2015). "Buccal, intranasal or
intravenous lorazepam for the treatment of acute convulsions in childen
in Malawi: An open randomized trial." African Journal o f Emergency
Medicine 5:
120-126.
Introduction: Acute convulsions in children are a common
emergency worldwide. Benzodiazepines are the recommended first line
treatment. Intravenous lorazepam is inexpensive, long acting and the
first line drug in resource-rich settings. However, comparable efficacy
by other routes of administration is unknown. We wished to compare the
efficacy of lorazepam by the buccal, intranasal or intravenous route in
the treatment of acute seizures in Malawian children. Methods: A
prospective, open-label, randomised, non-inferiority trial was performed
in children aged 2 months to 14 years presenting to the Queen Elizabeth
Central Hospital in Blantyre, Malawi with acute seizures lasting longer
than 5 min. Children were randomly assigned to receive lorazepam, 0.1
mg/kg, by the buccal, intranasal or intravenous route. The primary
endpoint was seizure cessation within 10 min of drug administration.
Results: There were 761 seizures analysed, with 252 patients in the
buccal, 245 in the intranasal and 264 in the intravenous groups.
Intravenous lorazepam stopped seizures within 10 min in 83%, intranasal
lorazepam in 57% (RR 2.46, CI 1.82–3.34), and the buccal route in 46%
(RR 3.14, CI 2.35–4.20; p= 0.001) of children. There were no significant
cardio-respiratory events and no difference in mortality or neurological
deficits. The study was halted after an interim analysis showed that the
primary endpoint had exceeded the protocol-stopping rule. Conclusions:
Intravenous lorazepam effectively treats most childhood seizures in this
setting. Intranasal and buccal routes are less effective but may be
useful in prehospital care or when intravenous access cannot be
obtained. Further studies comparing intranasal lorazepam to other
benzodiazepines, or alternative doses by a nonintravenous route are
warranted.
Maglalang, P. D., D. Rautiola, et al. (2018). "Rescue therapies for
seizure emergencies: New modes of administration." Epilepsia
59 Suppl 2: 207-215.
Mahmoudian, T. and M. M. Zadeh (2004).
"Comparison of intranasal midazolam with intravenous diazepam for
treating acute seizures in children." Epilepsy Behav 5(2): 253-5.
Midazolam, a water-soluble benzodiazepine, is usually given intravenously in status epilepticus. The aim of this study was to determine whether intranasal midazolam is as safe and effective as intravenous diazepam in the treatment of acute childhood seizures. Seventy children aged 2 months to 15 years with acute seizures (febrile or afebrile) admitted to the pediatric emergency department of a general hospital during a 14-month period were eligible for inclusion. Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.2 mg/kg were administered after intravenous lines were established. Intranasal midazolam and intravenous diazepam were equally effective. The mean time to control of seizures was 3.58 (SD 1.68) minutes in the midazolam group and 2.94 (SD 2.62) in the diazepam group, not counting the time required to insert the intravenous line. No significant side effects were observed in either group. Although intranasal midazolam was as safe and effective as diazepam, seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Intranasal midazolam can possibly be used not only in medical centers, but also in general practice and at home after appropriate instructions are given to families of children with recurrent seizures.
McGlone, R. and M. Smith (2001). "Intranasal
midazolam. An alternative in childhood seizures." Emerg Med J
18(3): 234.
BACKGROUND: Rapid treatment of status epilepticus (SE) is associated with better outcomes. Diazepam and midazolam are commonly used, but the optimal agent and administration route is unclear. OBJECTIVES: The objective was to determine by systematic review if nonintravenous (non-IV) midazolam is as effective as diazepam, by any route, in terminating SE seizures in children and adults. Time to seizure cessation and respiratory complications was examined. METHODS: We performed a search of PubMed, Web of Knowledge, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, American College of Physicians Journal Club, Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, and International Pharmaceutical Abstracts for studies published January 1, 1950, through July 4, 2009. English language quasi-experimental or randomized controlled trials comparing midazolam and diazepam as first-line treatment for SE, and meeting the Consolidated Standards of Reporting Trials (CONSORT)-based quality measures, were eligible. Two reviewers independently screened studies for inclusion and extracted outcomes data. Administration routes were stratified as non-IV (buccal, intranasal, intramuscular, rectal) or IV. Fixed-effects models generated pooled statistics. RESULTS: Six studies with 774 subjects were included. For seizure cessation, midazolam, by any route, was superior to diazepam, by any route (relative risk [RR] = 1.52; 95% confidence interval [CI] = 1.27 to 1.82). Non-IV midazolam is as effective as IV diazepam (RR = 0.79; 95% CI = 0.19 to 3.36), and buccal midazolam is superior to rectal diazepam in achieving seizure control (RR = 1.54; 95% CI = 1.29 to 1.85). Midazolam was administered faster than diazepam (mean difference = 2.46 minutes; 95% CI = 1.52 to 3.39 minutes) and had similar times between drug administration and seizure cessation. Respiratory complications requiring intervention were similar, regardless of administration route (RR = 1.49; 95% CI = 0.25 to 8.72). CONCLUSIONS: Non-IV midazolam, compared to non-IV or IV diazepam, is safe and effective in treating SE. Comparison to lorazepam, evaluation in adults, and prospective confirmation of safety and efficacy is needed.
Mula, M. (2017). "New Non-Intravenous Routes for Benzodiazepines in
Epilepsy: A Clinician Perspective." CNS Drugs
31(1): 11-17.
Benzodiazepines represent the first-line treatment for the acute
management of epileptic seizures and status epilepticus. The emergency
use of benzodiazepines must be timely, and because most seizures occur
outside of the hospital environment, there is a significant need for
delivery methods that are easy for nonclinical caregivers to use and
administer quickly and safely. In addition, the ideal route of
administration should be reliable in terms of absorption. Rectal
diazepam is the only licensed formulation in the USA, whereas rectal
diazepam and buccal midazolam are currently licensed in the EU. However,
the sometimes unpredictable absorption with rectal and buccal
administration means they are not ideal routes. Several alternative
routes are currently being explored. This is a narrative review of data
about delivery methods for benzodiazepines alternative to the
intravenous and oral routes for the acute treatment of seizures.
Unconventional delivery options such as direct delivery to the central
nervous system or inhalers are reported. Data show that intranasal
diazepam or midazolam and the intramuscular auto-injector for midazolam
are as effective as rectal or intravenous diazepam. Head-to-head
comparisons with buccal midazolam are urgently needed. In addition, the
majority of trials focused on children and adolescents, and further
trials in adults are warranted.
Neff, C., S. M. Joyce, et al. (2006). "Efficacy
and safety of intranasal midazolam administration by EMS personnel for
seizures and sedation." NAEMSP Winter abstracts.
Nunley, S., P. Glynn, et al. (2018). "Healthcare Utilization
Characteristics for Intranasal Midazolam Versus Rectal Diazepam." J
Child Neurol 33(2):
158-163.
To investigate connections between patient demographics, health care utilization, prescription use, and refills for patients using intranasal midazolam, per rectum diazepam, or both. A retrospective cohort contained patients with epilepsy prescribed intranasal midazolam, per rectum diazepam, or both. We analyzed number of emergency department visits, ambulance services, urgent care visits, and unplanned hospitalizations. A total of 5458 patients were identified. Patients on intranasal midazolam had on average 1.53 fewer emergency department visits (95% confidence interval 1.16-1.89, P < .0001), 0.29 fewer uses of ambulance services (95% confidence interval 0.17-0.41, P < .0001), and 0.60 fewer urgent care visits (95% confidence interval 0.36-0.83, P < .0001) compared to patients in the per rectum diazepam group. Patients with commercial insurance were more likely to have intranasal midazolam prescription (odds ratio = 1.73, 95% confidence interval 1.42-2.11, P < .0001). The results substantiate the cost-effective benefits of prescribing intranasal midazolam compared to per rectum diazepam because several aspects of health care utilization were decreased in those using intranasal midazolam.
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.
RATIONALE: About 20 per 100,000 children have convulsive status epilepticus
every year, a life-threatening condition. Benzodiazepines are the
first-line treatment for prolonged and recurrent seizures. Our study was
designed to gain understanding of caregiver perception of acute seizure
treatments. METHODS: Our project uses a cross-sectional survey study
design using the electronic medical record and a survey at a large
academic tertiary children's medical center. Subjects were patients with
epilepsy prescribed intranasal (IN) midazolam and/or per rectum (PR)
diazepam. The survey was administered to caregivers of children with
epilepsy regarding information on the comfort, efficacy, ease of use,
and time of administration for patients receiving both abortive seizure
medications. Exact binomial tests were employed to determine whether or
not differences in caregiver preference exist. RESULTS: One hundred and
sixty responses were obtained. Incomplete and duplicate surveys were
excluded, leaving 153 responses. Of those responses, 59 respondents
reported administering both medications. Among parents who expressed a
preference for one medication over the other, more parents felt overall
greater comfort with IN midazolam compared with rectal diazepam
(p=0.0004 and p=0.001), IN midazolam was perceived as easier to use
(68%, p=0.0038 and 74%, p=0.0004) and more effective (87%, p<0.0001)
than rectal diazepam. Intranasal midazolam was found to be superior to
rectal diazepam in several other categories as well. CONCLUSIONS: These
parents of children with epilepsy report increased ease of use, comfort,
and efficacy with IN midazolam as compared with rectal diazepam
suggesting that a readily available form of IN midazolam would be well
received in the pediatric population.
O'Regan, M. E., J. K. Brown, et al. (1996).
"Nasal rather than rectal benzodiazepines in the management of acute
childhood seizures?" Dev Med Child Neurol 38(11): 1037-45.
Benzodiazepines are routinely used by the rectal route for the treatment of acute epileptic seizures: if a benzodiazepine was absorbed from nasal administration this could provide a more acceptable alternative to rectal administration. Nineteen children (age range 7 months to 14 years) with intractable epilepsy were chosen. The EEG's showed unequivocal epileptic activity persisting during the recording. The midazolam was dripped slowly into the anterior nares. Fifteen had a positive response, a dramatic improvement in their EEG or cessation of fits. Drug induced beta activity occurred in 14 children. The mean time to appearance of beta activity was 111.5 secs (SD = 95.3 secs). The reduction in spike count pre and post midazolam was statistically significant (p 0.01). The improvement in EEG background was also statistically significant. Midazolam is absorbed via the i.n. route. With the dosages used it suppressed epileptic activity and produced an improvement in EEG background. The children and parents found the method acceptable. This is the first study to use the i.n. route for anti-convulsant drugs.
O'Regan, M. E., J. K. Brown, et al. (1996).
"Nasal rather than rectal benzodiazepines in the management of acute
childhood seizures? [see comments]." Dev Med Child Neurol 38(11):
1037-45.
Benzodiazepines are routinely used by the rectal route for the treatment of acute epileptic seizures: if a benzodiazepine was absorbed from nasal administration this could provide a more acceptable alternative to rectal administration. Nineteen children (age range 7 months to 14 years) with intractable epilepsy were chosen. The EEG's showed unequivocal epileptic activity persisting during the recording. The midazolam was dripped slowly into the anterior nares. Fifteen had a positive response, a dramatic improvement in their EEG or cessation of fits. Drug induced beta activity occurred in 14 children. The mean time to appearance of beta activity was 111.5 secs (SD = 95.3 secs). The reduction in spike count pre and post midazolam was statistically significant (p < 0.01). The improvement in EEG background was also statistically significant. Midazolam is absorbed via the i.n. route. With the dosages used it suppressed epileptic activity and produced an improvement in EEG background. The children and parents found the method acceptable. This is the first study to use the i.n. route for anti-convulsant drugs.
Ostendorf, A. P., K. Merison, et al. (2018). "Decreasing Seizure
Treatment Time Through Quality Improvement Reduces Critical Care
Utilization." Pediatr Neurol
85: 58-66.
BACKGROUND: Rapid, effective treatment for status epilepticus reduces associated morbidity and mortality, yet medication delivery remains slow in many hospitalized patients. We utilized quality improvement (QI) methodology to improve treatment times for hospitalized children with status epilepticus. We hypothesized rapid initial seizure treatment would decrease seizure morbidity. METHODS: We utilized QI and statistical process control analysis in a nonintensive care setting within a tertiary care pediatric hospital. We performed Plan-Do-Study-Act cycles including (1) revising the nursing process for responding to seizures, (2) emphasizing intranasal midazolam over intravenous lorazepam, (3) relocating medications and supplies, (4) developing documentation tools and reinforcing correct processes, (5) developing and disseminating an online education module for residents and nurse practitioners, and (6) completing standardization to intranasal midazolam. RESULTS: Seventeen months after starting the project, 66 seizures had been treated with a benzodiazepine in a median (p25-p75) time of 7.5 minutes (5 to 10), decreased from a baseline of 14 minutes (8-30) (P = 0.01). The proportion of patients receiving a benzodiazepine in 10 minutes or less improved from 39% to 79%. The proportion of patients transferred to intensive care decreased from a baseline of 39% to 9% (P < 0.005), resulting in an estimated $2.1 million in mitigated hospital charges. Significant harm did not occur during the implementation of these interventions. CONCLUSIONS: Children with status epilepticus were treated with benzodiazepines more rapidly and effectively following implementation of QI methodology. These interventions reduced utilization of critical care and mitigated hospital charges.
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.
OBJECTIVE: The objective of the study was to compare the performance of
intravenous (IV) lorazepam (IVL) and intranasal midazolam (INM) for
seizure termination and prevention of seizure clusters in adults
admitted to the epilepsy monitoring unit (EMU) in whom seizures were
captured on continuous video-electroencephalogram. METHODS:
Retrospective cohort of consecutive adults (>/=18years) with epilepsy
admitted to the EMU at a single tertiary academic center, who
experienced epileptic seizures (confirmed electroencephalographically)
and required rescue therapy. The study spanned from January 2015 until
December 2016, which included one year before and one year after
transitioning from IVL to INM as the standard rescue therapy at our
institution. RESULTS: A total of 50 subjects received rescue therapy and
were included in the analysis. In the first year, out of 216 patients
with epilepsy admitted to the EMU, 27 (13%) received IVL; in the second
year, 23/217 (11%) received INM. There were no differences in baseline
characteristics and markers of epilepsy severity, the median duration of
index seizure (1.7min [interquartile range (IQR): 1.1-2.7] in IVL vs.
2.0min [IQR: 1.5-2.6] in INM group, p=0.20), or in the number of
subjects requiring repeat benzodiazepine administrations (IVL 8/27
[29.6%] vs. INM 7/23 [30.4%], p=0.95). There were no differences in the
median number of recurrent seizures in 24h (1 [IQR: 1-3] in IVL vs. 2
[IQR: 1-4] in INM, p=0.27), occurrence of status epilepticus (IVL 4/27
[14.8%] subjects vs. INM 1/23 [4.3%] subjects, p=0.36), incidence of
seizure clusters (IVL 8/27 [29.6%] subjects vs. INM 7/23 [30.4%]
subjects, p=0.95), need for transfer to an intensive care unit (ICU), or
other adverse events. SIGNIFICANCE: In our retrospective study, INM was
comparable with IVL for seizure termination and prevention of seizure
clusters in the adult EMU. Intranasal midazolam circumvents the need for
IV access to be maintained throughout hospitalization and is an
attractive alternative to IVL as a rescue therapy in this setting.
Ideally, future large, prospective, randomized, and double blind studies
are needed to confirm these findings.
Perez, A., R. Clark, et al. (2000).
"Out-of-hospital management of patients who are having seizures: Is
there a need for an alternative to intravenous therapy? (abstract)."
Ann Emerg Med 36(4): S38, abstract 144.
Phillips, B. and R. Appleton (2001). "Intranasal
midazolam for treating febrile seizures in children. Safety is as
important as efficacy." Bmj 322(7278): 107-8.
Rey, E., J. M. Treluyer, et al. (1999).
"Pharmacokinetic optimization of benzodiazepine therapy for acute
seizures. Focus on delivery routes." Clin Pharmacokinet 36(6):
409-24.
All benzodiazepines enter cerebral tissue rapidly. However, the duration of action is short for diazepam ( 2 hours) and midazolam (3 to 4 hours) and longer for clonazepam (24 hours) and lorazepam (up to 72 hours), and is not correlated with the plasma concentration-time profiles of these drugs. Although a relationship between the plasma concentration of diazepam, lorazepam and midazolam and their pharmacodynamic effect has been demonstrated in healthy individuals, some caution is warranted as the clinical relevance of these data has not been clearly established. The physicochemical properties of benzodiazepines (lipid solubility and protein binding) regulate their rate and extent of entry into the brain and cerebrospinal fluid. However, the duration of the pharmacological activity of benzodiazepines may be in part related to the affinity of these compounds for the benzodiazepine receptors in the brain: midazolam, clonazepam and lorazepam have higher affinities than diazepam. In the emergency setting, the intravenous route is the most suitable, delivering adequate quantities of benzodiazepines as fast as possible. However, when intravenous administration is not available, rectal administration of a solution is a convenient method for diazepam, midazolam being the only one of these drugs that should be given intramuscularly. The assessment of the efficacy of benzodiazepines in the management of acute seizures and status epilepticus is mainly based on nonrandomized uncontrolled trials. According to the route of administration, the efficacy was 28.6 to 100% (intrarectal) and 54 to 100% (intravenous) for diazepam, 82 to 100% (intravenous) for lorazepam, and 79% (intranasal), 93 to 100% (intramuscular) and 100% (intravenous) for midazolam. Although diazepam was initially chosen for the management of refractory status epilepticus, the longer duration of action of lorazepam and clonazepam may favour the use of these 2 drugs. However, double-blind evaluations are necessary to determine which drug is best.
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.
OBJECTIVE: To quantify the cost-effectiveness of rescue
medications for pediatric status epilepticus: rectal diazepam, nasal
midazolam, buccal midazolam, intramuscular midazolam, and nasal
lorazepam. METHODS: Decision analysis model populated with effectiveness
data from the literature and cost data from publicly available market
prices. The primary outcome was cost per seizure stopped ($/SS). One-way
sensitivity analyses and second-order Monte Carlo simulations evaluated
the robustness of the results across wide variations of the input
parameters. RESULTS: The most cost-effective rescue medication was
buccal midazolam (incremental cost-effectiveness ratio ([ICER]:
$13.16/SS) followed by nasal midazolam (ICER: $38.19/SS). Nasal
lorazepam (ICER: -$3.8/SS), intramuscular midazolam (ICER: -$64/SS), and
rectal diazepam (ICER: -$2,246.21/SS) are never more cost-effective than
the other options at any willingness to pay. One-way sensitivity
analysis showed the following: (1) at its current effectiveness, rectal
diazepam would become the most cost-effective option only if its cost
was $6 or less, and (2) at its current cost, rectal diazepam would
become the most cost-effective option only if effectiveness was higher
than 0.89 (and only with very high willingness to pay of $2,859/SS to
$31,447/SS). Second-order Monte Carlo simulations showed the following:
(1) nasal midazolam and intramuscular midazolam were the more effective
options; (2) the more cost-effective option was buccal midazolam for a
willingness to pay from $14/SS to $41/SS and nasal midazolam for a
willingness to pay above $41/SS; (3) cost-effectiveness overlapped for
buccal midazolam, nasal lorazepam, intramuscular midazolam, and nasal
midazolam; and (4) rectal diazepam was not cost-effective at any
willingness to pay, and this conclusion remained extremely robust to
wide variations of the input parameters. SIGNIFICANCE: For pediatric
status epilepticus, buccal midazolam and nasal midazolam are the most
cost-effective nonintravenous rescue medications in the United States.
Rectal diazepam is not a cost-effective alternative, and this conclusion
remains extremely robust to wide variations of the input parameters.
Scheepers, M., B. Scheepers, et al. (2000). "Is
intranasal midazolam an effective rescue medication in adolescents and
adults with severe epilepsy?" Seizure 9(6): 417-22.
The aim of this study was to determine whether intranasal midazolam is a safe and effective rescue medication in adolescent and adult patients with severe epilepsy. This field trial was designed to test the feasibility of the use of intranasal midazolam as an alternative to rectal diazepam in a cohort of patients with severe epilepsy who require rescue medication as part of their treatment. A dose of intranasal midazolam (5 mg if the patient weighed less than 50 kg and 10 mg if the patient weighed over 50 kilograms) was prescribed for those who had previously responded to other rescue medication. Midazolam was prescribed buccally if excessive head movement accompanied seizures. The protocol reverted to the usual rescue medication if there was no response to midazolam within 10 minutes. Vital signs were monitored for half an hour following the administration of the treatment. Twenty-two patients received 84 treatment episodes and 79 of these were considered clinically effective. Five treatment failures were recorded, three due to poor technique in delivering the midazolam. Two patients were successfully retried on midazolam and a third is awaiting a retrial of this drug. The two other treatment failures received the drug buccally. In the first patient the clinical opinion was that this was possibly a psychogenic non-epileptic seizure. The other patient responded initially, but within an hour had another seizure requiring further rescue treatment. No significant adverse effects were reported. Our study shows that intranasal midazolam, when used appropriately, is an effective treatment in those who require rescue treatment. There are clear advantages in the use of midazolam over diazepam in the treatment of acute seizures. These include the favourable pharmacokinetic and pharmacodynamic properties of midazolam as well as the potential of a more acceptable and dignified administration route.
Scheepers, M., B. Scheepers, et al. (1998).
"Midazolam via the intranasal route: an effective rescue medication for
severe epilepsy in adults with learning disability." Seizure
7(6): 509-12.
People with a learning disability are often disadvantaged due to the nature of their disability. Up to a third are likely to have concomitant epilepsy which adds to the health loss experienced by this group. It is important to manage their epilepsy in such a way as to limit the debilitating effects of both the illness and the medication. Rectal diazepam remains the gold standard rescue medication for prolonged, recurrent seizures or seizures associated with hypoxia. Some of the drawbacks are highlighted in this paper and we go on to explore a novel means of treating these seizures. Midazolam, via the intranasal route, has been used extensively in children, mostly as a sedative but also in the treatment of epilepsy. We present two cases, both are adults with a learning disability, who have benefited significantly from the use of intranasal midazolam. Ongoing research into the safe use of this form of treatment, training of staff and carers and the impact on the individual is being conducted.
Scott, R. C., F. M. Besag, et al. (2001).
"Intranasal midazolam for treating febrile seizures in children. Buccal
midazolam should be preferred to nasal midazolam." Bmj 322(7278):
107.
Scott, R. C., B. G. Neville, et al. (1997).
"Nasal rather than rectal benzodiazepines in the management of acute
childhood seizures? [letter; comment]." Dev Med Child Neurol
39(2): 137-8.
Silbergleit, R., V. Durkalski, et al. (2012). "Intramuscular versus
intravenous therapy for prehospital status epilepticus." N Engl J Med
366(7): 591-600.
BACKGROUND: Early termination of prolonged seizures with
intravenous administration of benzodiazepines improves outcomes. For
faster and more reliable administration, paramedics increasingly use an
intramuscular route. METHODS: This double-blind, randomized,
noninferiority trial compared the efficacy of intramuscular midazolam
with that of intravenous lorazepam for children and adults in status
epilepticus treated by paramedics. Subjects whose convulsions had
persisted for more than 5 minutes and who were still convulsing after
paramedics arrived were given the study medication by either
intramuscular autoinjector or intravenous infusion. The primary outcome
was absence of seizures at the time of arrival in the emergency
department without the need for rescue therapy. Secondary outcomes
included endotracheal intubation, recurrent seizures, and timing of
treatment relative to the cessation of convulsive seizures. This trial
tested the hypothesis that intramuscular midazolam was noninferior to
intravenous lorazepam by a margin of 10 percentage points. RESULTS: At
the time of arrival in the emergency department, seizures were absent
without rescue therapy in 329 of 448 subjects (73.4%) in the
intramuscular-midazolam group and in 282 of 445 (63.4%) in the
intravenous-lorazepam group (absolute difference, 10 percentage points;
95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority
and superiority). The two treatment groups were similar with respect to
need for endotracheal intubation (14.1% of subjects with intramuscular
midazolam and 14.4% with intravenous lorazepam) and recurrence of
seizures (11.4% and 10.6%, respectively). Among subjects whose seizures
ceased before arrival in the emergency department, the median times to
active treatment were 1.2 minutes in the intramuscular-midazolam group
and 4.8 minutes in the intravenous-lorazepam group, with corresponding
median times from active treatment to cessation of convulsions of 3.3
minutes and 1.6 minutes. Adverse-event rates were similar in the two
groups. CONCLUSIONS: For subjects in status epilepticus, intramuscular
midazolam is at least as safe and effective as intravenous lorazepam for
prehospital seizure cessation. (Funded by the National Institute of
Neurological Disorders and Stroke and others; ClinicalTrials.gov number,
ClinicalTrials.gov NCT00809146.).
To
compare the
efficacy of
intranasal midazolam
in relation
to intravenous midazolam for control of seizures. To observe
variability if any amongst
the two
groups in
terms of
heart rate,
respiratory rate,
blood pressure and
oxygen saturation.
A Prospective
Randomized study
conducted on
100 patients
of 0-19
years of
age hospitalized
in emergency ward and NICU in a convulsing state. They
were divided into two groups. GP-I was given intranasal midazolam
@ 0.3 mg/ kg and GP-II was given intravenous midazolam @ 0.3 mg/ kg.
Outcome was measured in
terms of:
Time taken
from physician
contact to
drug administration.
Time taken from drug administration to cessation of seizures.
Mean time from
physician contact
to drug
administration was
significantly shorter
with intranasal
midazolam as
compared to
intravenous midazolam
viz [ 0.40+
0.10min vs
1.06+0.40+min) [p<
0.05 ].Mean
time from
drug administration
to cessation of
seizures was
comparable in
both the groups
1.0 +
0.31 min
and 1.0+0.32
min (p>
0.05). However
this difference was
statistically
insignificant. The
readings for
oxygen saturation and
vital parameters
did not
show a
statistically
significant difference
amongst the
groups. Seizure
control
was more
prompt with
intranasal midazolam
as compared
to intravenous
midazolam. As
time needed for
drug administration
was lesser.
Intranasal midazolam
is a rapid,
efficacious, easy to administer and socially more acceptable route of
drug administration. It can
be used not only in hospital setting but also for home management of
seizures after proper instructions to parents.
Sperling, M. R., K. F. Haas, et al. (2014). "Dosing feasibility and
tolerability of intranasal diazepam in adults with epilepsy."
Epilepsia 55(10): 1544-1550.
OBJECTIVE: To determine the feasibility of administering a diazepam nasal
spray formulation (diazepam-NS) to adults with epilepsy during a
generalized tonic-clonic seizure or in the postictal period following a
tonic-clonic or other seizure type, to assess pharmacokinetics and to
assess tolerability. METHODS: An open-label study was conducted in
patients admitted to the epilepsy monitoring unit. Eligible patients
received a single dose of diazepam-NS approximating 0.2 mg/kg. Plasma
diazepam concentrations were measured serially up to 12 h postdose, and
maximum observed plasma concentration (Cmax ); time to maximum
concentration (Tmax ); and the area under the plasma concentration-time
curve for time zero to last sampling time (AUC0-12 ) were estimated and
dose-normalized. Pharmacodynamic assessments included Kaplan-Meier
analysis to determine the time-to-next seizure. Safety and tolerability
were assessed. RESULTS: Of the 78 patients who consented, 30 had
treatment and pharmacokinetic data. Ten patients were treated during a
convulsive tonic-clonic seizure, seven within 5 min following the last
clonic jerk, and 13 in the postictal period >/=5 min after a tonic-clonic
or following other seizure-types. Diazepam median Tmax was 45 min.
Dose-normalized mean Cmax and AUC0-12 values of diazepam were comparable
among patients regardless of the timing of diazepam-NS administration in
relation to seizure. Of those treated, 65% were seizure-free during the
12-h observation period and 35% had post-dose seizures. Treatment was
well tolerated, with no unexpected safety findings: 74% had mild and 25%
had moderate adverse events. Nasopharyngeal signs were resolved by 12 h
postdose. SIGNIFICANCE: Diazepam can be delivered in effective
therapeutic concentrations by a nasal spray device during the convulsive
phase of tonic-clonic seizures or in the postictal periods following
tonic-clonic or other seizure types.
Terry, D., A. D. Patel, et al. (2016). "Barriers to Seizure
Management in Schools: Perceptions of School Nurses."
J Child Neurol.
The purpose of this study was to assess school nurses' perceptions of
barriers to optimal management of seizures in schools. Eighty-three
school nurses completed an electronic survey. Most agreed they felt
confident they could identify a seizure (97.6%), give rectal diazepam
(83.8%), and handle cluster seizures (67.1%), but fewer were confident
they could give intranasal midazolam (63.3%), had specific information
about a student's seizures (56.6%), or could swipe a vagus nerve
stimulator magnet (47.4%). Nurses were more likely to be available at
the time of a seizure in rural (17/20) (85%) versus suburban (21/34)
(62%) or urban (8/25) (32%) schools (P = .001). School nurses are
comfortable managing seizures in the school setting. However, a specific
seizure plan for each child and education on intranasal midazolam and
vagus nerve stimulator magnet use are needed. A barrier in urban schools
is decreased availability of a nurse to identify seizures and administer
treatment.
Thakker, A. and P. Shanbag (2012). "A randomized controlled
trial of intranasal-midazolam versus intravenous-diazepam for acute
childhood seizures." J Neurol.
The
objective of this study is to compare the safety and efficacy of
midazolam given intranasally with diazepam given intravenously in the
treatment of acute childhood seizures. A randomized controlled study was
conducted in a pediatric emergency department in a tertiary general
hospital. Fifty children aged from 1 month to 12 years presenting with
acute seizures of at least 10 min duration were enrolled during a 12
month period. Intranasal midazolam (0.2 mg/kg) and intravenous diazepam
(0.3 mg/kg) were administered. The main outcome measures were interval
between arrival at hospital and starting treatment and interval between
arrival at hospital and cessation of seizures. Intranasal midazolam and
intravenous diazepam were equally effective. Overall 18 of 27 seizures
were controlled with midazolam and 15 of 23 with diazepam. The mean
interval between arrival at hospital and starting treatment was
significantly shorter in the midazolam group [3.37 min (SD 2.46)] as
compared to the diazepam group [14.13 min (SD 3.39)]. The mean interval
between cessation of seizures and arrival at hospital was significantly
shorter in the midazolam group [6.67 min (SD 3.12)] as compared to the
diazepam group [17.18 min (SD 5.09)]. The mean interval between control
of seizures and administration of the drug was shorter in the diazepam
group [2.67 min (SD 2.31)] as compared to the midazolam group [3.01 min
(SD 2.79)]. No significant side effects were observed in either group.
Seizures were controlled more quickly with intravenous diazepam than
with intranasal midazolam. Midazolam was as safe and effective as
diazepam. The overall interval between arrival at hospital and cessation
of seizures was shorter with intranasal midazolam than with intravenous
diazepam. The intranasal route can be possibly used not only in medical
centres, but with appropriate instruction by the parents of children
with acute seizures at home.
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.
INTRODUCTION: Seizures count to critical situations emergency medical
systems (EMS) are confronted with. OBJECTIVES: Evaluation of a modified
treatment algorithm (MTAS-EMS) using diazepam and midazolam due to a
supply bottleneck of iv lorazepam in 2012. METHODS: Retrospective study
where data from patients treated for seizures by the EMS of the city of
Zurich were analyzed. Effectiveness of the MTAS-EMS and i.v. diazepam in
children and adults was compared with respect of cessation of seizure
without recurrence over the period until arrival at the hospital. The
chi-square and Fisher's exact test were used to compare categorical
data. The Student's t-test and Mann Whitney test were used to compare
numerical data. p-values < 0.05 are considered significant. RESULTS: Of
584 documented missions, 165 treated patients (126 adults and 39
children) were included. 115 patients (80 adults and 35 children) were
treated according the MTAS-EMS. Cessation of seizure was achieved in 85%
of the adults and in 97% of the children, if all options of the MTAS-EMS
were used. The first dose of nasal midazolam was more successful in
children compared to adults (p = 0.012). In adults, the single dose of
i.v. diazepam terminated the seizure in 98% (p = 0.001) compared to 57%
for the single dose of iv and 64% for nasal midazolam. CONCLUSIONS: The
treatment success of the MTAS-EMS is high. However, in adults the single
dose of i.v. diazepam is as successful as the completely used MTAS-EMS
and seems to be superior to the single dose iv and nasal midazolam.
Click here for link to the full thesis
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Walker, Dm, et al. (2006). "Update on the acute
management of status epilepticus in children." Curr Opin Pediatr
18(3): 239-244.
PURPOSE OF REVIEW: Status epilepticus is the most common neurologic emergency in children. The understanding of its less recognizable forms, its pharmacologic management, the role of electroencephalography and the long-term morbidity and mortality as a result of status epilepticus are consistently evolving. This review frames the current understanding of several issues as they apply to acute management in the emergency department. RECENT FINDINGS: Researchers are working to define less recognizable forms of status epilepticus such as nonconvulsive, autonomic and psychogenic. Buccal and intranasal forms of midazolam are emerging as suitable alternatives to rectal diazepam in the initial treatment of status epilepticus. Valproic acid, chloral hydrate and newer-generation antiepileptics are being proposed as safe and effective alternatives to the traditional drugs used to treat status epilepticus. The role of electroencephalography in diagnosis is being elucidated. Risk factors for neurologic sequelae and mortality after status epilepticus remain an area of research with conflicting findings and no real consensus. SUMMARY: The understanding of different types of status epilepticus, the options for pharmacologic treatment, the tools for diagnosis and the morbidity and mortality of the disease are still evolving. As a result, several areas for further research remain that will help clinicians in their approach to this complex condition.
Wallace, S. J. (1997). "Nasal benzodiazepines
for management of acute childhood seizures?" Lancet 349(9047):
222.
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.
Wassner, E., B. Morris, et al. (2001).
"Intranasal midazolam for treating febrile seizures in children. Buccal
midazolam for childhood seizures at home preferred to rectal diazepam."
Bmj 322(7278): 108.
Wilson, M. T., S. Macleod, et al. (2004).
"Nasal/buccal midazolam use in the community." Arch Dis Child
89(1): 50-1.
A telephone survey was carried out to evaluate the effectiveness and convenience of nasal/buccal midazolam in terminating prolonged seizures in the community. A total of 33/40 (83%) families who had used it found it effective and easy to use; 20/24 (83%) preferred using midazolam to rectal diazepam.
Wolfe, T.R., T Macfarlane. (2006). "Intranasal
midazolam therapy for pediatric status epilepticus." Am J Emerg Med
24(3): 343-6.
Prolonged seizure activity in a child is a frightening experience for families as well as care providers. Because duration of seizure activity impacts morbidity and mortality, effective methods for seizure control should be instituted as soon as possible, preferably at home. Unfortunately, parenteral methods of medication delivery are not available to most caregivers and rectal diazepam, the most commonly used home therapy, is expensive and often ineffective. This brief review article examines recent research suggesting that there is a better way to treat pediatric seizures in situations where no intravenous access is immediately available. Intranasal midazolam, which delivers antiepileptic medication directly to the blood and cerebrospinal fluid via the nasal mucosa, is safe, inexpensive, easy to learn by parents and paramedics, and provides better seizure control than rectal diazepam.
Wolfe, T. R. and E. D. Barton (2003). "Reducing
needlestick risk: Nasal drug delivery in EMS." J Emerg Med Serv JEMS
28(12): 52-63.
Wolfe, T. R. and T. Bernstone (2004).
"Intranasal drug delivery: an alternative to intravenous administration
in selected emergency cases." J Emerg Nurs 30(2): 141-7.
Zelcer, M. and R. D. Goldman (2016). "Intranasal midazolam for seizure
cessation in the community setting." Can Fam Physician
62(7): 559-561.
QUESTION: There are times when parents arrive to my clinic after their
child has had a seizure and a second seizure takes place in the clinic.
While waiting for transport to the hospital, are there ways to stop the
seizures without the need to obtain intravenous access in the clinic?
ANSWER: Intravenous diazepam has been a first-line therapy to stop
seizures in children for many years. Other routes of drug administration
such as intramuscular, rectal, and buccal are available but have several
limitations. More evidence suggests that the intranasal route to
administer drugs is quick and effective in children, and the use of
midazolam has been continuing to show promise in seizure cessation. With
its good safety profile, intranasal midazolam can be used in the clinic
and prehospital setting for seizure cessation in children.