Status epilepticus (SE) is a medical emergency that requires immediate care, as the disease is associated with substantial mortality and morbidity rates (1–3). In practice, SE is defined as any seizure lasting at least 5 mins or two or more seizures in succession without a return to baseline between episodes (4, 5). Current guidelines recommend benzodiazepines as initial treatment for SE regardless of type. When administered early after seizure onset, benzodiazepines have a 79% efficacy rate in stopping seizures (6).

Benzodiazepines can be administered through various routes: midazolam is preferred for intramuscular administration, while lorazepam is preferred for intravenous (IV) administration (4, 5). The risk of refractory SE increases with prolonged seizures, making inadequate dosing of benzodiazepines potentially harmful to patient outcomes (3). Despite well-established guidelines on the appropriate benzodiazepine dosage, underdosing is quite common in clinical settings, which has led to poor seizure control and worse patient outcomes (7–11).

Previous studies have shown a widespread lack of compliance with benzodiazepine dosage. A 2017 retrospective analysis of 170 adult and pediatric emergency department (ED) patients revealed that only 11% of patients received the recommended dose of benzodiazepine; these were all pediatric patients (12). Another observational study of 44 adult patients with generalized convulsive status epilepticus (GCSE) revealed that only one patient received the adequate dose of benzodiazepine (13). Another retrospective study assessed 222 adult patients who received 403 doses of benzodiazepines. Of these, only 1.5% were treated according to recommended guidelines (9). A secondary analysis was undertaken to describe the pattern of benzodiazepine use: the Established Status Epilepticus Treatment Trial (ESETT) found that the first dose of benzodiazepine was lower than the guideline dosing recommendation for 76% of midazolam administrations and 81% of lorazepam administrations (11). A 2022 study involving 111 adult patients found that 55% of the patients did not receive an appropriate dose of benzodiazepine (10). These results highlight the propensity for underdosing benzodiazepine in patients with SE.

Several reasons may explain the widespread underdosing observed in patients with SE. Betjemann et al. (2) noted that a significant number of emergency medical service protocols in California did not adhere to evidence-based guidelines, with initial MDZ doses often being lower than those recommended. Another possible explanation is that the diagnoses had not yet been determined by the emergency department physicians in these cases. Patients may have been experiencing SE or simply recovering from recent seizures. In addition, concerns about benzodiazepine-induced respiratory depression contribute to subtherapeutic dosing levels (14–16). Alldredge et al. (17, 18) found that the rate of respiratory and circulatory adverse effects in SE patients who received a placebo was two-fold higher than in patients who received benzodiazepines. Similarly, a cross-sectional study reported that higher doses of MDZ administered by emergency medical service personnel to adult patients with SE did not lead to an increased need for respiratory support (18).

In Saudi Arabia, active epilepsy affects roughly 6.5 people per thousand (19). The substantial burden of this disease necessitates further investigation. Despite the gravity of the disease, widespread treatment errors are reported–specifically with regard to benzodiazepine dosing. To the best of our knowledge, no other studies have explored the dosing assessment of benzodiazepines for treatment of status epilepticus in Saudi Arabia. This knowledge gap makes it difficult to ascertain whether current practices align with international standards or adequately meet the needs of the Saudi population. The rationale for focusing on the Saudi context is based on the limited availability of region-specific data, which underscores the need for context-sensitive research. Moreover, variations in healthcare infrastructure, clinical practice patterns, and patient demographics may influence treatment outcomes. These factors underscore the importance of examining the local adherence to management guidelines within the Saudi healthcare setting. Therefore, the objective of this study was to assess benzodiazepine dosing in SE patients presented to the ED and assess clinical outcomes in relation to the appropriateness of benzodiazepine dosing.

In total, 196 patients were included in this study. Prehospital benzodiazepine administration occurred in 5% of cases. One-hundred and twenty seven patients (64.7%) received lorazepam, 40 (20.4%) received midazolam, and 29 (14.7%) received diazepam. A total of 38.7% (n = 76) of the patients received at least two separate doses of benzodiazepines. The mean dose of benzodiazepine administered was 2.1 mg LE (range: 0.5–4 mg). The cumulative mean benzodiazepine dose in our cohort was 0.034 mg/kg LE (95% confidence interval, 0.031 to 0.036 mg/kg).

In this retrospective study of 196 patients presented to the ED with SE, only 17% received an adequate first dose of benzodiazepines. Our findings are generally consistent with results of other published trials, revealing a pattern of benzodiazepine underdosing in clinical practice (7, 9–11, 20). Sathe et al. (7) analyzed pre-enrollment data from the ESETT and found that of 102 subjects who received their first dose of benzodiazepine in the ED, only 29.8% met the minimum recommended guidelines. Similarly, Weant et al. (9) observed that only 1.5% of 222 patients who received 403 benzodiazepine doses for GCSE in the ED adhered to the guidelines. Braun et al. (10) reported that 54.7% of 111 patients with SE did not receive the recommended minimum dose of 4 mg of LE. Similarly, Kohle et al. (20) found that only 21.6% of 328 patients with SE met the current dosing guidelines. A likely reason that the underdosing rates observed in our study were higher than those reported in previous studies is the strict, weight-based parameters applied in the inadequate dosing definition. This weight-based threshold may have resulted in a more stringent classification of underdosing compared to other studies. Our study revealed higher rates of inadequate dosing: 96.6, 90, and 77.2% for diazepam, midazolam, and lorazepam, respectively. Similarly, Sathe et al. (11) examined 460 initial benzodiazepines doses administered to patients with SE and found that 76% of midazolam and 81% of lorazepam administrations were below the recommended doses. This pattern of systematic underdosing persists across multiple geographical regions. Possible explanations for the widespread benzodiazepine underdosing in SE may stem from multiple factors, including delayed recognition of SE, uncertainty regarding the applicability of dosing recommendation guidelines across SE subtypes, and limited familiarity with weight-based dosing in adults. Furthermore, clinicians are concerned about adverse effects, such as respiratory depression and oversedation. Of all treatments evaluated, lorazepam showed the lowest rate of inadequate dosing (77.2%). This may be explained by its frequent use and greater familiarity among providers. In our study, lorazepam was also the most commonly administered benzodiazepine (64.7% of cases), likely contributing to better adherence to recommended dosing guidelines.

The mean duration of mechanical ventilation after the first dose of benzodiazepine was 4 days with no significant differences between the groups. However, this contrasts the findings of Kohle et al. (20), which revealed that patients with GCSE benefited from adequate benzodiazepines dosing due to significantly shortened mechanical ventilation durations (37.1 vs. 208 h). This discrepancy may be explained by differences in the demographics of the study population. Our cohort had a relatively young mean age (32 years) and a high prevalence of a seizure history (82.1%). Factors such as age and SE severity are strong predictors of functional SE outcomes, potentially obscuring the risks that might emerge with benzodiazepine underdosing (20).

Notably, results showed that inadequate total benzodiazepine dosage was significantly associated with increased in-hospital mortality rates (p = 0.01). Variations in patient populations and dosing standard interpretations could explain such discrepancies compared from previous studies (10, 11, 20). However, these findings should be interpreted with a degree of caution as further prospective studies are necessary to draw substantive conclusions. In addition, there is no strong evidence to support a statistically significant association between guideline-appropriate benzodiazepine dosing, whether first dose or total dose, and in-hospital mortality. Further prospective studies with larger sample sizes are needed to confirm these findings and provide more definitive conclusions.”

The consistent finding of widespread benzodiazepine underdosing in SE management in our cohort and across multiple studies underscores the urgent need for interventions to enhance adherence to the established dosing guidelines. This is particularly critical, as it suggests a link between inadequate benzodiazepine dosing and poor clinical outcomes. These findings highlight several high-priority targets for quality improvement initiatives, which may include development of institution-specific treatment protocols and rigorous implementation of standardized, evidence-based dosing protocols that clearly define appropriate dosing. In addition, healthcare institutions must establish clear policies mandating adherence to these protocols, fostering interdisciplinary collaboration and integrating clinical decision support within electronic health records to prevent under-dosing and medication errors. Lastly, ongoing provider education on appropriate dosing of benzodiazepines can help ensure competency and cultivate a culture of medication safety.

This study had several limitations. First, the fact that it was a single-center, retrospective design limits our ability to generalize from the findings. The study was conducted at a tertiary academic medical center in Saudi Arabia. However, further studies involving larger, more diverse populations from multiple centers across Saudi Arabia are warranted to corroborate these results. In addition, as it relies on the ED physician’s diagnosis at the time of therapy, some patients may have experienced non-epileptic events. However, this does not affect the primary objective of assessing adherence to the benzodiazepine guidelines. Furthermore, because of the retrospective nature of the study, the dosing and sequence of medication administration may have been skewed during the post-event documentation process. The potential inaccuracy of patient weight data (as some weights may have been estimated rather than directly measured), may have influenced subsequent dosage classifications. Lastly, the etiology of status epilepticus remains an important prognostic factor that may influence treatment outcomes; as such, it warrants further research.

In conclusion, our findings suggest that benzodiazepine underdosing in SE remains a common phenomenon in patients with SE. Appropriate benzodiazepine dosing may be achieved through the implementation of institution-specific protocols and focused educational initiatives on weight-based administration of benzodiazepines.