Diazepam is a long acting, highly lipid-soluble BDZ with a half-life of 20–100 h. It is available in PO, IV, IM, and PR formulations. The onset of action is 1–5 min after IV administration. It is rapidly absorbed and then rapidly enters the brain. The duration of peak effect is 15–60 min. Although its half-life is long, the duration of antiepileptic effect is relatively short due to its rapid redistribution to other body tissues (adipose tissue and muscle). Therefore, even after the fall of diazepam levels in the brain, the sedative effects persist. With repeated administration of diazepam, there is accumulation within adipose tissue, thereby prolonging the systemic side effects of the medication. Diazepam has an active metabolite. The recommended IV dose is 0.15 mg/kg (up to 10 mg) at a rate of ≤5 mg/min [8]. This dose can be repeated in 5 min if seizures persist. IV administration of diazepam can result in local tissue irritation, venous phlebitis or thrombosis, and injection site pain. The use of diazepam for prolonged IV administration is covered in another chapter.

Rectal diazepam can be considered for ICU patients if IV access has been lost. The recommended PR dose for adults is 0.2 mg/kg, for children 6–11 years is 0.3 mg/kg, and for children 2–5 years is 0.5 mg/kg. Diazepam has a Class IIa, level A recommendation from the Neurocritical Care Society for emergent management of SE.

Lorazepam is a high-potency BDZ and is the drug of choice for the emergent management of seizures. Because it is less lipid-soluble than diazepam (and thus subject to less redistribution to body tissues) and has a high degree of protein binding, there is a longer duration of peak effect than diazepam. It is available in PO, IM, and IV formulations. The half-life is 10–20 h, with an anticonvulsant effect of 6–12 h. Due to its longer anticonvulsant effect, lorazepam is the drug of choice for alcohol withdrawal seizures.

Lorazepam is recommended as a Class I, level A medication for the initial management of SE by the Neurocritical Care Society [8]. The recommended dose is 0.1 mg/kg (rate of 2 mg/min IV push) with a maximum dose of 4 mg per dose. A second dose can be repeated in 5–10 min if seizures persist [8]. The use of lorazepam for prolonged IV administration is covered in another chapter. As with any BDZ, serious adverse effects can include respiratory depression and hypotension. The IV formulation of lorazepam contains the solvent, propylene glycol, which is known to cause hypotension and arrhythmias. Propylene glycol toxicity (arrhythmias, hypotension, and a clinical picture similar to sepsis) is a concern with prolonged high-dose administration of lorazepam. Lorazepam has an active metabolite. With mild-to-moderate renal or hepatic impairment, lorazepam should be used with caution. There is a tendency for tolerance to develop with BDZ treatment, therefore it is recommended that long term maintenance AEDs be administered in addition to BDZs.

In the VA Cooperative Study , the success rate for IV lorazepam was 65% for the control of overt GCSE [25]. In a randomized, double-blinded, placebo-controlled trial, IV lorazepam resulted in seizure control in 89% vs. 76% with IV diazepam for patients presenting with “convulsive, absence, partial elementary or partial complex status epilepticus” [33]. Although lorazepam has been associated with a lower risk of cardiac and respiratory depression than diazepam, this study showed similar rates of adverse cardiopulmonary complications (lorazepam 10.6% vs. diazepam 10.1%). In a study of treatment for out-of-hospital SE, lorazepam was more effective than diazepam or placebo for termination of SE (59% vs. 43% and 21%, respectively) [32]. Lorazepam has also been shown to be effective in pediatric SE. In 2008, a Cochrane Review of drug management of GTC seizures, including GCSE, in the pediatric population found that IV lorazepam is as effective as IV diazepam (70% vs. 65%, respectively), but has fewer side effects [34].

The body of literature for the treatment of NCS and NCSE with lorazepam is limited. A 2011 survey of neurologists found that lorazepam is used as first-line treatment of NCSE by 44% of respondents and by 28% of respondents for NCS [35], highlighting the observation that NCSE is typically treated more aggressively than NCS.

Midazolam is a short acting BDZ (half-life of 1–4 h) that is available in IV, IM, and transmucosal (nasal, buccal, and rectal) formulations. Midazolam is highly water-soluble, leading to rapid absorption when administered by the IV and IM routes. Due to its water-solubility, it is unlikely to cause thrombophlebitis with IV administration and makes midazolam the most attractive BDZ for IM administration. Unlike lorazepam, propylene glycol is not a component for midazolam formulations; therefore, arrhythmias are not encountered with midazolam administration. Midazolam is metabolized in the liver by the cytochrome P450 (CYP450) system [36]. Other medications used in ICU patients that are also metabolized by the CYP450 system can affect the metabolism of midazolam. Midazolam is 96% protein-bound and undergoes renal excretion. Due to rapid redistribution after absorption, IV midazolam has a very short anticonvulsant effect of <5 min, leading to a high probability of seizure recurrence with bolus dosing. However, patients in the ICU may have an expanded volume of distribution, resulting in a longer half-life of midazolam, especially in liver dysfunction [37]. IM midazolam has a longer anticonvulsant effect (2 h). Due to the short anticonvulsant effect of midazolam, other BDZs (lorazepam and diazepam) are more often used for the emergent treatment of seizures in the ICU.

A double blind, randomized controlled trial of IM midazolam versus IV lorazepam in prehospital treatment of adult and pediatric SE by paramedics found that IM midazolam was statistically superior to IV lorazepam (73% vs. 63% seizure cessation, respectively) [38]. The rate of respiratory depression requiring intubation was similar between groups. Although there is a faster onset of action with lorazepam, the requirement for IV placement by paramedics offset the delayed onset of action of IM midazolam.

There is little data supporting the use of bolus dosing of midazolam in NCS and NCSE in critically ill patients. A 2010 survey of neurologists found that only 3% of respondents use midazolam for first-line treatment of NCS and 7% for first-line treatment of NCSE. In the ICU, midazolam is used more commonly as an infusion for coma induction for the treatment of refractory NCS and NCSE [35].

The Neurocritical Care Society has given IM midazolam a Class I, level A recommendation for the emergent treatment of SE [39]. The recommended dosing is 0.2 mg/kg IM (maximum 10 mg IM) in adults. For pediatrics, the recommended dosing as follows: 10 mg IM for >40 kg and 5 mg IM for 13–40 kg. Intranasal and buccal administration of midazolam is not encountered in the ICU. The dosing of midazolam for prolonged IV administration and the advantages of midazolam over other BDZs for prolonged infusions is covered in another chapter. Patients should be monitored closely for respiratory depression and hypotension after administration of IM midazolam . For patients in the ICU without IV access, IM midazolam can be considered for first-line therapy for convulsive or nonconvulsive seizures or SE.

Although clonazepam is a potent BDZ with a high affinity for the GABA_A receptor, it is rarely used in the ICU for seizure management due to the lack of an available IV formulation in the USA. It is highly lipid-soluble, therefore resulting in rapid anticonvulsant effects and has a longer half-life (10–20 h) than all other BDZs previously discussed. Clonazepam does not have a recommendation by the Neurocritical Care Society for the treatment of SE.