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Comparison of intranasal versus intravenous midazolam for management of status epilepticus in dogs: A multi‐center randomized parallel group clinical study

Abstract Background The intranasal (IN) route for rapid drug administration in patients with brain disorders, including status epilepticus, has been investigated. Status epilepticus is an emergency, and the IN route offers a valuable alternative to other routes, especially when these fail. Objectives To compare IN versus IV midazolam (MDZ) at the same dosage (0.2 mg/kg) for controlling status epilepticus in dogs. Animals Client‐owned dogs (n = 44) with idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin manifesting as status epilepticus. Methods Randomized parallel group clinical trial. Patients were randomly allocated to the IN‐MDZ (n = 21) or IV‐MDZ (n = 23) group. Number of successfully treated cases (defined as seizure cessation within 5 minutes and lasting for ≥10 minutes), seizure cessation time, and adverse effects were recorded. Comparisons were performed using the Fisher's exact and Wilcoxon rank sum tests with statistical significance set at α < .05. Results IN‐MDZ and IV‐MDZ successfully stopped status epilepticus in 76% and 61% of cases, respectively (P = .34). The median seizure cessation time was 33 and 64 seconds for IN‐MDZ and IV‐MDZ, respectively (P = .63). When the time to place an IV catheter was taken into account, IN‐MDZ (100 seconds) was superior (P = .04) to IV‐MDZ (270 seconds). Sedation and ataxia were seen in 88% and 79% of the dogs treated with IN‐MDZ and IV‐MDZ, respectively. Conclusions and Clinical Importance Both routes are quick, safe, and effective for controlling status epilepticus. However, the IN route demonstrated superiority when the time needed to place an IV catheter was taken into account.

Animals: Client-owned dogs (n = 44) with idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin manifesting as status epilepticus.
Methods: Randomized parallel group clinical trial. Patients were randomly allocated to the IN-MDZ (n = 21) or IV-MDZ (n = 23) group. Number of successfully treated cases (defined as seizure cessation within 5 minutes and lasting for ≥10 minutes), seizure cessation time, and adverse effects were recorded. Comparisons were performed using the Fisher's exact and Wilcoxon rank sum tests with statistical significance set at α < .05.

| INTRODUCTION
Status epilepticus is an emergency that requires rapid and effective delivery of anti-seizure drugs. Rapid treatment is crucial to avoid primary and secondary brain injury and systemic complications. Because of the anatomical and physiological properties of the nasal cavity as well as its potential to circumvent the blood-brain barrier (BBB), the intranasal (IN) route might offer an advantageous and novel way to directly and quickly deliver drugs to the brain to treat various disorders. [1][2][3][4][5][6][7] Intranasal drug delivery has been widely investigated for anesthetic purposes, and experimental studies have reported that it can be effectively used for analgesia (IN-fentanyl), 8 sedation (IN-xylazine, 9 IN-medetomidine/ketamine, 10 IN-ketamine, 11,12 ) and sedation and opioid reversal (IN-atipamezole/IN-naltrexone). 13 Benzodiazepines (eg, midazolam [MDZ]), are used commonly as a first-line management option for status epilepticus in humans and dogs. 14-23 Midazolam, a water-soluble benzodiazepine, is considered an effective and safe anti-seizure drug when administered by the IN, IV, or IM routes. 15,18,[20][21][22][23][24] Intranasal MDZ can be useful or even life-saving, especially when IV access is not available. 15,25 Intranasal MDZ has been reported to be an effective and safe choice as a sedative drug in children undergoing diagnostic and minor surgical procedures. [26][27][28][29] It also has been shown to suppress epileptic spike activity on electroencephalograms of epileptic children. 30 Based on clinical trials, which evaluated the efficacy of IN-MDZ, it was concluded that IN-MDZ was effective and safe for terminating status epilepticus in humans and that it can be used not only by clinicians in the hospital environment but also by families at home. 22,31 It was recently demonstrated that IN-MDZ was effective and safe as well as superior to rectally administered diazepam for the management of status epilepticus in dogs with idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin. 15 In the present study, we compared MDZ given at the same dose but by different routes (IN or IV) for the treatment of status epilepticus in dogs. Our aim was to provide further evidence of the potential efficacy and safety of IN-MDZ in dogs with status epilepticus and compare it to the gold standard of IV administration to evaluate if a significant difference existed between the 2 routes in the time needed to terminate the epileptic seizures.

| MATERIALS AND METHODS
The methodology we used was similar to that of a previous trial of IN-MDZ, which has been described previously. 15 The current study was an open-label randomized parallel group clinical trial including clientowned dogs and approved by the enrolling universities' ethical committees. Owner information and consent forms for the study were completed. Dogs with status epilepticus manifesting generalized or focal epileptic seizures with any type of motor activity (ie, tonic-clonic or myoclonic) caused by idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin were included. Dogs with reactive seizures associated with metabolic or toxic causes or dogs that had received any drugs before 5 minutes of continuous epileptic seizure activity had passed were excluded. Classification of epilepsy types, clinical signs, and diagnostic approach were based on the International Veterinary Epilepsy Task Force consensus reports. 32,33 In particular, for the diagnosis of idiopathic epilepsy, classification into 3 tiers of confidence was performed based on history, signalment, and unremarkable interictal neurological examination, blood tests, brain magnetic resonance imaging, and cerebrospinal fluid analysis. 33 Status epilepticus was defined as a continuous epileptic seizure lasting more >5 minutes, or ≥2 discrete epileptic seizures between which incomplete recovery of consciousness occurred. 32 Dogs that manifested status epilepticus were randomly assigned to IN-MDZ or IV-MDZ groups, using randomized sealed envelopes. Midazolam was administered at the same dosage for both routes (ie, 0.2 mg/kg) after at least 5 minutes of continuous seizure activity. In the dogs allocated to the IV-MDZ group, an IV catheter, if not already present, was placed immediately. In the IN-MDZ group, an IV catheter was placed after MDZ administration to provide IV access. All dogs were treated and remained in a hospital environment for constant observation and monitoring for at least 1 hour after benzodiazepine administration.

| Primary outcomes
The outcome measurements included: 1. "Seizure cessation" time, defined as the time between drug administration and seizure cessation.  was >10 minutes. 15 For the unsuccessful cases, the protocol was no longer applicable and additional anti-seizure drugs could be given as directed by the clinician in charge.

| Secondary outcomes
The outcome measurements included: 1. Complications and adverse effects. Heart rate and rhythm, respiratory rate and pattern, blood pressure (by use of Doppler) and oxygen saturation (by use of pulse oximetry) were measured 5 (T5) and 3. Further information, such as history of antiepileptic drugs and duration of dogs' seizure activity before inclusion in the trial, was recorded.

| Statistical analysis
As in a previous trial, 15 the primary outcomes evaluated were the number of successful cases in each group and seizure cessation times.
Statistical analysis was conducted using the statistical software R (version 3.5.2). Significance was set at α ≤ .05. The number of successfully treated cases per group was compared between the 2 groups (IV or IN) using a Fisher's exact test. The remaining outcomes ("seizure cessation" time, "doctor-to-drug" time, and "total seizure cessation" time) were compared using a Wilcoxon rank sum test. Continuous variables are reported as median and range.

| Signalment and baseline characteristics of study subjects and disease characterization
Details of signalment, clinical findings, and disease characteristics of the included cases are provided in Table 1.  was quicker than IV-MDZ, and the difference was significant when the time to place an IV catheter was taken into account. Lastly, a metaanalysis in human patients concluded that although there was minimal difference in the time interval from drug administration to clinical seizure cessation, which was shorter for diazepam by any route than for non-IV MDZ by any route, this difference was not clinically relevant. 51 Increasing interest in IN drug administration as a therapeutic option for brain and systemic diseases derives from the particular anatomical, physiological, and histological characteristics of the nasal cavity. Intranasal administration provides an opportunity for rapid systemic drug absorption and rapid onset of action as well as different and advantageous pathways through which the drug can reach the brain. 3,6,[52][53][54][55][56][57] The canine nasal cavity is divided by the nasal septum into 2 symmetric airways, each including the nasal vestibule, respiratory and olfactory regions. 58 The nasal vestibule has limited vascularization and permeability, which leads to poor absorption of substances such as drugs. 7,58,59 In contrast, the respiratory and olfactory regions have high vascularization and good permeability and, therefore, are the main sites of drug absorption. 7,58 Although lipid-soluble small molecules can be absorbed more easily from the nasal cavity, many drugs targeting the brain are water-soluble small molecules or large molecules (>400 Da) that cannot freely pass through various mucosal barriers of the body including the nasal mucosa.

| Primary and secondary outcomes
Midazolam is water-soluble (marketed solution pH = 3.5) but, after IN administration, becomes lipid-soluble (nasal cavity pH = 5.5-6.5 1,60 ), and as a result it can cross the nasal mucosa and pass into the brain with a rapid onset of action. 25,61,62 After absorption, some amount of the drug will undergo clearance and drainage by the systemic circulation and nasal lymphatic vessels, and might not reach the brain. 52 The remaining amount passes into the circulation and reaches the BBB without being subject to the first-pass hepatic metabolism, which can enhance the drug's bioavailability. 22,25,[62][63][64][65][66][67] The BBB is an essential factor limiting the development of new drugs targeting the brain because it can restrict the influx of drugs into the brain. All large molecules (ie, >400 Da) and >98% of small molecules cannot penetrate the BBB 6,54 and therefore cannot achieve adequate therapeutic concentrations in the brain after IV or PO administration. 68  and multidrug-resistance-associated protein). [77][78][79] Some molecules can avoid the BBB, enter the brain, and then be distributed to other brain areas from the point of entry, via the olfactory (within olfactory epithelium) and trigeminal (within respiratory epithelium) nerves. 52,56,57,80 Various mechanisms of transport via these nerve pathways have been described. 56,57,81 Final distribution of the drug after brain entry points at the level of the olfactory bulb (via the olfactory nerve and nasal epithelium) and the brainstem (via the trigeminal nerve) to other areas of the brain is likely established by intracellular and extracellular transport mechanisms. [82][83][84][85] Apart from the properties and advantages that the IN route offers to the administration of drugs that target the brain, another important aspect is the formulation and delivery method of the drug (ie, the nasal device). These factors can influence uptake of the drug by the brain. In our trial, similar to a previous study, 15 we used the MAD used in humans, to deliver the medication into the nasal cavity. This MAD is a type of a spray device that can be used like a syringe and delivers the drug as a very fine mist of 30-100 μm particles, enhancing the drug's absorption and bioavailability. 86,87  ations with regard to a drug's absorption and delivery to the brain, the IN route offers several potential advantages. These include rapid use and onset of action, non-invasive and easy administration, a safe and effective method directly targeting the brain, and the ability to overcome the BBB. Further preclinical and clinical studies (including a larger number of subjects and different devices and drug dosages) focusing on this promising route should be performed to establish this therapeutic route for various brain disorders in dogs.