Intranasal Midazolam versus Rectal Diazepam for the Management of Canine Status Epilepticus: A Multicenter Randomized Parallel-Group Clinical Trial.

Abstract

Companion Notes

Multicenter, randomized, parallel-group clinical trial comparing intranasal midazolam and rectal diazepam for status epilepticus in 35 dogs

Introduction on status epilepticus

- occur in dogs either at home or during hospitalization

- status epilepticus

- can be caused by the following:

- toxic causes

- metabolic causes

- structural brain disease

- also occurs as manifestation of idiopathic epilepsy

- estimated 20-60% of affected dogs have at least 1 episode in their lifetime

- estimated case fatality rate: 25.3-38.5%

- benzodiazepines

- diazepam (DZP) and midazolam (MDZ) are common first-line options

- for status epilepticus in humans and dogs

- less common administration routes may be helpful

(especially when IV access is not available)

- rectal (R)

- intranasal (IN)

- intramuscular (IM)

- buccal or sublingual

- DZP commonly used as a first- or second-line medication

- R-DZP is relatively easy and quick for owners or veterinarians to use

- evidence on efficacy is contradictory

- in 1 study, therapeutic plasma levels not attained quickly enough

(to effect emergency seizures)

- in 1 clinical trial, it was effective for generalized cluster seizures

- in human medicine:

- in several clinical trials on IN-MDZ in people with emergency seizures

- with or without comparison to R-DZP

- IN-MDZ effective and safe in the hospital and home settings

- in human trials on emergency epileptic seizures

- IN benzodiazepines superior to R for terminating those seizures

Study design

- study population:

- dogs with idiopathic or structural epilepsy manifesting status epilepticus

- within a hospital environment

- procedure:

- dogs with status epilepticus were treated immediately

- they were assumed to have been already seizuring for > 5 minutes

- dogs randomly allocated to 1 of 2 treatment groups

- IN-MDZ, 20 dogs

- MDZ injectable solution (5 mg/mL), 0.2 mg/kg intranasally

- using mucosal atomization device (MAD)

- syringe (1 mL or 3 mL) attached to atomizer

- turns medication into a fine mist (30-100 µm)

- if present, excessive nasal secretions quickly removed with gauze

- if administered dose > 1 ml, drug given via both nostrils

- MAD device's dead space taken into account

- history & signalment

- median age: 5.1 years of age with a range of 0.5-7

- breeds accounting for 10% or more of population

- German shepherd dog, 15%

- golden retriever, 11%

- R-DZP, 15 dogs

- DZP injectable solution (5 mg/mL), 1 mg/kg per rectum

- needleless syringe as deep as possible into rectum

- history & signalment

- median age: 4.8 years of age with a range of 0.9-6.8

- breeds accounting for 10% or more of population

- German shepherd dog, 13%

- Labrador retriever, 12%

- golden retriever, 10%

- dogs were first included in the trial and then treated

- if testing indicated reactive seizures, dogs were excluded

- 3 dogs initially enrolled were subsequently excluded

- presumed intoxication, 2 dogs

- seizures due to hypoglycemia, 1 dog

- seizure cessation time and adverse effects recorded

(time between drug administration and seizure cessation)

- successful treatment defined as seizures that ceased within 5 minutes

- and did not recur within 10 minutes after administration

Results

- status epilepticus terminated

- IN-MDZ: 70% (14/20)

- median "seizure cessation" time: 47 seconds with a range of 6-280

- relapse, 11 successful cases

- median "seizure relapse" time: 904 seconds

- no relapse, 3 successful cases

- R-DZP: 20% (3/15) (P = .0059)

- median "seizure cessation" time: 214 seconds with a range of 204-290

- relapse, all successful cases

- median "seizure relapse" time: 645 seconds

- adverse effects

- sedation and ataxia, all dogs

- brief episode of sneezing, 7 IN-MDZ dogs

- diagnosis

- idiopathic epilepsy, 21 of the 35 (60%)

- structural epilepsy, 12 (34%)

- neoplasia, 7

- meningoencephalitis of unknown origin (MUO), 5

- epilepsy of unknown origin, 2

“In this study, IN-MDZ was significantly more effective than R-DZP for terminating status epilepticus in a hospital environment. It is likely that this finding could be extrapolated to at-home treatment of emergency seizures before hospital admittance and, as such, IN-MDZ might be a more appropriate and effective prehospital seizure management method than R-DZP.”