How to Use Midazolam to Control Equine Neonatal Seizures

1. Introduction

Control of acute onset seizures in neonatal foals has conventionally relied on short-term (immediate) control using IV/IM bolus administration of diazepam. Recurrent seizures in foals have been treated with either repeated diazepam administration and/or infusion of phenobarbital or phenytoin [1]. Single seizure episode control with diazepam is frequently effective, relatively inexpensive, and simple; however, recurrent seizures become more difficult to manage. Respiratory depression, which is more severe in neonates because of their reduced hepatic clearance, makes longer term seizure control with phenobarbital problematic in both a practice or referral institution setting. The onset of activity may be 15 min or more after IV administration, with a peak effect not present until 60 min after administration. Other potential deleterious effects of phenobarbital use include bradycardia, hypotension, and hypothermia, particularly at larger doses. Because of this, slow titration using small IV boluses (2 - 3 mg/kg, IV, over 15 - 20 min) of the drug and close observation are required to find the lowest effective dose. Ideally, phenobarbital use in foals should be implemented in conjunction with monitoring of plasma drug concentration. Therapeutic concentrations are reported at 5 - 30 μg/ml. The clearance of phenobarbital is slow in the neonate, and the effects are prolonged after administered. Complete evaluation of central nervous system (CNS) function may be delayed for several days after cessation of phenobarbital because of its prolonged effects.

The potential for drugs, such as phenobarbital, to complicate the clinical management of neonatal seizures led to the search for alternative means for seizure control. Midazolam is a potent short-acting benzodiazepine that is a safe and highly effective agent for controlling status epilepticus; it has been investigated in the treatment of refractory (i.e., phenobarbital and/or phenytoin resistant) neonatal seizures in human infants [2-5]. It is reported to be more potent per milligram than diazepam in a seizure model in dogs [6]. The use of midazolam as a first-line treatment in seizure management has gained popularity with some equine neonatologists.

2. Materials and Methods

Midazolam can be administered IV, IM, or continuous rate infusion (CRI) to foals with seizures. For immediate seizure control, IV midazolam can be used. Rapid IV administration can cause hypotension and a period of apnea; therefore, it is desirable to watch the foal after rapid IV administration. Alternatively, the same dose can be given IM. In other species, absorption is rapid, and time to onset of effect is short [7]. The usual IV or IM dose to a 50-kg foal ranges from 2 to 5 mg and can be repeated as needed. The smallest effective dose should be used.

Foals that have more persistent seizures and repetitive seizures that require frequent dosing may be maintained with a CRI. A CRI requires that the foal have an IV catheter with a fluid pump. The CRI is made using 100-ml bags of 0.9% saline. Ten milliliters of saline are removed, and 10 ml of 5 mg/ml (50 mg) midazolam is injected into the bag, creating a final solution of 0.5 mg/ml. The midazolam solution is then administered at a rate of 2 - 6 ml/h (1 - 3 mg/h) to the 50-kg foal using the fluid pump and appropriate IV lines. The infusion rate can be altered as needed to maintain control of seizure activity, but it should be kept low enough that the foal is rousable and not at an anesthetic plane of sedation. The CRI can be discontinued when desired, and the foal should be alert within 1 - 2 h, allowing for assessment of neurologic status. The CRI can then be reinitiated, if needed. CRI is generally not needed for >24 - 72 h. Light-sensitive midazolam should be protected from sources of light, but many clinics do not wrap lines or bags containing midazolam and report no change in efficacy.

3. Results

A non-scientific survey of equine neonatologists worldwide suggested that use of midazolam in seizure control is increasing and is becoming the agent of first choice with some practitioners. The general impression is that midazolam produces a smooth and rapid control of seizures in many equine neonates and that control can be maintained by additional IM doses or by CRI, if needed. The biggest advantage to most surveyed practitioners was the ability to "waken" the foal readily, assess the neurologic function, and return it to a sedated state easily. This contrasts with the almost uniform frustration with the use of phenobarbital, where practitioners felt that foals remained stuporous or sleepy for too long and that neurologic assessment was impossible for several days after its use. Other concerns with phenobarbital use are significant respiratory depression, effects on blood pressure, and thermoregulation, which make case management more complex and sometimes require that the foals be placed on a mechanical ventilator for a period of time. This is in contrast to the minimal, if any, noted side effects of midazolam use.

4. Discussion

Midazolam seems to be an effective and reasonable alternative to phenobarbital in the management of single, recurrent, or persistent equine neonatal seizures. Its use in equine neonatal intensive care units is increasing because of its apparent safety and efficacy, although no formal pharmacologic studies have been performed to date regarding the use of this drug in foals.

The author thanks Drs. Jane Axon, Catherine Herron, Daniela Bedenice, and Darien Feary for sharing their experiences with midazolam use in equine neonatal intensive care.