Year: 2007
Type: article
Abstract: The incidence of status epilepticus that occurs in the out-of-hospital setting as compared to in hospital is unknown, but it is certainly the case that far more episodes of status epilepticus begin without the presence of trained health care personnel. Given the recognition that treatment of status epilepticus should be initiated as soon as possible, there is a compelling need to have effective therapies that can be initiated in the out-of-hospital setting by first-responders. Thus, most paramedics and other first-responders in emergency medical services systems are provided instruction and guidelines concerning the recognition and management of status epilepticus, and family members of patients prone to acute repetitive seizures or status epilepticus are often provided with “rescue medications” (such as rectal diazepam or sublingual lorazepam). In this presentation, we will review a few of the key studies demonstrating the effectiveness of drug treatment of status epilepticus or acute repetitive seizures in the out-of-hospital setting, and current research aimed at the development of new and more effective modes of drug delivery. A 1995 report by Alldredge and colleagues (Alldredge et al., 1995) was one of the first to look systematically at the experience of administering antiepileptic drugs to children in the out-of-hospital setting. They found that prehospital diazepam therapy (either rectal or intravenous) was associated with status epilepticus of shorter duration and a reduced likelihood of recurrent seizures in the emergency department, and no increased risk of complications related to therapy. This study was followed by the Prehospital Treatment of Status Epilepticus (PHTSE) trial, considered to be the most definitive study of the effectiveness of drug treatment of generalized, convulsive status epilepticus in adults by paramedics in the out-of-hospital setting (Alldredge et al., 2001; Lowenstein et al., 2001). PHTSE was a randomized, double-blind trial comparing intravenous diazepam, lorazepam, or placebo in 205 patients. The results showed a clear, unambiguous benefit of active treatment with either diazepam or lorazepam over placebo, with a trend favoring lorazepam over diazepam. Furthermore, the rates of respiratory or circulatory complications after study treatment were highest in the placebo group. Importantly, despite treatment in the out-of-hospital setting, a substantial number of patients arrived at the destination hospital still in status epilepticus, emphasizing the need for even more effective approaches to treatment. Two other large, controlled trials have helped define the benefits of drug treatment of prolonged or repetitive seizures in the out-of-hospital setting. Dreifuss and colleagues conducted a randomized, double-blind, placebo-controlled study of home-based treatment of acute repetitive seizures in children and adults (Dreifuss et al., 1998). They found that rectal diazepam was superior to placebo in reducing seizure frequency and leading to an improved overall outcome as assessed by the caregiver. There were no significant differences in adverse events between the groups (and no reports of respiratory or circulatory complications), although somnolence was more common in the diazepam group and six patients in the placebo group required anticonvulsant treatment at a medical facility for continuing seizures. In 1999, Scott et al. described the results of a randomized trial of buccal midazolam and rectal diazepam for 79 episodes of status epilepticus in 28 children and young adults living at a residential school for the severely disabled. Buccal midazolam was at least as effective as rectal diazepam, and there were no clinically important adverse events in either group. Given the relative inconvenience and reduced social acceptability of administering medications per rectum, this study highlighted the potential value of oral and nasal routes of drug administration for seizures in the out-of-hospital setting. The choice of medications to treat status epilepticus or prolonged and repetitive seizures depends upon the capabilities of the caregiver, which, in turn, dictates the routes available for drug administration. Trained health care personnel are often able to administer drugs intramuscularly and intravenously, although there is occasionally difficulty in establishing intravenous access (Alldredge et al., 2001). Several studies have demonstrated that family caregivers can safely and accurately administer drugs by buccal, rectal, and nasal routes. Benzodiazepines as a class are the drugs of choice for treating seizure emergencies. The selection of a specific drug is determined by route of administration, physical chemical properties and pharmacokinetics. Diazepam (DZP), lorazepam (LZP), and midazolam (MDZ) have been used for out-of-hospital treatment of seizure emergencies. These three agents differ in their lipid solubility, distribution in the body, and elimination rate. As shown in Table 1, DZP and MDZ are 4 and 6 times more lipid soluble than LZP. With respect to MDZ, the commercial injectable formulation is buffered to a pH of 3 that produces an ionized open ring compound with a low octanol/water partition coefficient. Only when the drug reaches physiologic pH does MDZ revert to its highly lipid soluble structure. The elimination half-life of the three drugs varies from less than an hour to 1–2 days, which can affect the duration of activity. In addition, MDZ undergoes extensive first pass metabolism when the drug is administered by mouth or nasally. When administered as an intravenous injection, all 3 drugs rapidly enter the central nervous system because of the very large absorptive surface area of the brain. The resulting onset of effect occurs within 1–5 min (Arendt et al., 1983). However, DZP and MDZ quickly redistribute to muscle and fat tissue because they are 4–5 times more lipid soluble than LZP. In contrast, the pharmacodynamic effect of LZP will persist up to 30 min or more depending upon the dose, the nature of the seizure, and individual pharmacokinetics. When considering alternate routes of administration, selection of a benzodiazepine will differ from intravenous administration. Intramuscular, buccal, rectal, and nasal routes have several characteristics in common. All possess limited absorptive surfaces areas, which are approximately 200 cm2 or less from IM and small fluid volumes. Consequently, to attain the most rapid and complete absorption the drug should be highly lipid soluble and administered as a solution so as to bypass disintegration and dissolution processes. Rapid decline in brain concentrations tends not to be a problem when drugs are administered by these routes because distribution to the brain and other tissues occurs simultaneously. Under these conditions, MDZ is preferred for IM administration and DZP and MDZ are preferred for other routes. Intramuscular injection of midazolam results in rapid onset of effect, while times to maximum plasma concentrations following IM administration of LZP and DZP are relatively slow, averaging an hour or more (Greenblatt et al., 1982; Jawad et al., 1986; Wermeling et al., 2001). Jawad et al. compared the change in EEG spike activity following 10 or 15 mgs of IM MDZ vs. 10 or 20 mg of IV DZP. A significant and comparable reduction in spikes occurred within 5–15 min following IM MDZ. Scott et al. characterized the pharmacodynamics of buccal administration of the injectable MDZ formulation in healthy volunteers (Scott et al., 1998). EEG changes occurred within 5–10 min of administration of the drug, suggesting rapid absorption and onset of effect. Consistent and extensive absorption is predicated on keeping the solution in the buccal pouch, a requirement that may be difficult to meet when treating a seizure emergency. Moreover, there is concern that placement of an object or fingers in the mouth of a patient having a seizure runs counter to standard first aid advice. The rectal route of administration has been extensively studied. Among the three benzodiazepines, DZP displays the most rapid and consistent absorption due to its greater lipid solubility compared to LZP, and the low water content in the rectal cavity that slows the conversion of MDZ to its high lipid soluble form (Lombroso, 1989; Malinovsky et al., 1993; Cloyd et al., 1998; Scott et al., 1998; Wermeling et al., 2001). Therapeutic concentrations following rectal DZP are attained within 5–10 in children and within 10–15 min in adults (Lombroso, 1989; Cloyd et al., 1998). Several investigators have studied the bioavailability and tolerability of nasally administered benzodiazepines. DZP and MDZ exhibit more rapid absorption than LZP, with both drugs reaching maximum concentrations within 5–15 min (Malinovsky et al., 1993; Burstein et al., 1997; Wermeling et al., 2001; Knoester et al., 2002; Riss et al., 2006). Subjects in studies involving intranasal administration of commercial DZP or MDZ injectable formulations report considerable but transient discomfort. The nasal cavity is able to hold, at most, 0.5 ml of an externally instilled solution. The large volumes required in the administration of a clinically relevant dose of either DZP or MDZ using the commercial injectable formulations often result in leakage out of the nose or into the esophagus. This can delay or, in the case of MDZ, decrease absorption (Burstein et al., 1997; Knoester et al., 2002).
Source: Epilepsia
Authors: Daniel H. Lowenstein, James Cloyd
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1972605602