Intranasal Midazolam or Rectal Diazepam for Seizures?

Rectal administration of diazepam has been the mainstay for emergency management of seizures in the home environment or in situations where venous access has not yet been established; yet it is cumbersome, and studies have questioned whether therapeutic plasma concentrations can be achieved quickly enough to be effective. Conversely, prior pharmacokinetic studies on intranasal midazolam in healthy dogs have shown appropriate pharmacokinetic profiles and bioavailability.

Several studies in recent years have evaluated intranasal midazolam as an alternative to rectal diazepam, including this multicenter, randomized clinical trial that compared outcome data between the 2 treatments.

Study Design

This multicenter, randomized, parallel-group clinical trial compared seizure cessation time and adverse effects for rectal diazepam versus intranasal midazolam. A mucosal atomizer device was used to aerosolize the drug upon injection. Dogs of any age or breed with idiopathic, structural, or unknown causes of epilepsy were included in the study; dogs with reactive epilepsy were excluded. Epilepsy type and status epilepticus classification were according to the International Veterinary Epilepsy Task Force consensus report. As such, enrolled cases exhibited status epilepticus, in which seizure activity had persisted for longer than 5 minutes, and the dog received no medication during that time.

Randomization dictated which benzodiazepine protocol was to be administered, and medications were prepared during this 5-minute period of seizure activity. Intranasal midazolam was dosed at 0.2 mg/kg and administered using an atomizer. If the volume to be administered exceeded 1 mL, then the dose was divided between both nostrils. Rectal diazepam was administered at 1 mg/kg using a needle-less syringe inserted as deeply as possible rectally.

Once administered, patient outcomes were recorded as either a successful responder (onset of seizure cessation within 5 minutes or duration of seizure control >10 minutes without seizure relapse), or unsuccessful/nonresponder (onset of seizure cessation >5 minutes or duration of seizure control <10 minutes). Nonresponders were then administered 0.5 to 1.0 mg/kg intravenous diazepam. Adverse events, including but not limited to sedation, ataxia, and abnormal vital signs, as well as any administration difficulties, were recorded.

RELATED:

• Epilepsy Management Requires Substantial Commitment From Dog Owners
• A Review of Medical Cannabis

Results and Discussion

Thirty-five dogs were ultimately enrolled in the study after exclusion criteria were applied; 15 received rectal diazepam and 20 received intranasal midazolam. Enrolled cases were comprised of idiopathic epilepsy (n=21), neoplasia (n=7), meningoencephalitis of unknown origin (n=5), or epilepsy of unknown origin (n=2).

Overall, intranasal midazolam was significantly more effective than rectal diazepam in terms of seizure cessation time (0.8 vs. 3.5 minutes, respectively; P = .0059), a difference that was also present within the idiopathic epilepsy subgroup (P = .018). The time to relapse of seizure activity with intranasal midazolam was longer (15 minutes; range, 10-19 minutes) than with rectal diazepam (10.8 minutes; range, 10.6-11.2 minutes).

Severe sedation and ataxia were reported as adverse effects in all 15 dogs receiving rectal diazepam and in 7 of 20 (35%) dogs receiving intranasal midazolam. No signs of cardiopulmonary dysfunction were noted, including dyspnea, hypoventilation, cough, cyanosis, arrhythmia, hypertension, hypotension, or cardiac arrest. Reported administration difficulties included 2 dogs (13%) in the rectal diazepam group in which there was difficulty inserting the syringe during severe seizure activity, and 2 dogs (10%) in the intranasal midazolam group in which there was mild difficulty applying the atomizer.

Clinical Impact

Based on the results of this study, intranasal midazolam is safe and appears to have superior efficacy when compared with rectal diazepam in terms of seizure control and prolonging the time to seizure relapse. Administration was simple, and the adverse effects of sedation and ataxia were observed less commonly than with rectal diazepam.

Dr. Packer is an associate professor of neurology/neurosurgery at Colorado State University College of Veterinary Medicine and Biomedical Sciences in Fort Collins, and is board certified in neurology by the American College of Veterinary Internal Medicine. She is active in clinical and didactic training of veterinary students and residents and has developed a comparative neuro-oncology research program at Colorado State University.