Evaluation of the Safety of Rapid Administration of Undiluted High-Dose Intravenous Levetiracetam

Abstract

Background

Intravenous (IV) levetiracetam (LEV) is an antiseizure medication traditionally given as an intermittent infusion to mitigate potential adverse effects given its acidic formulation. The process of compounding may lead to delays in treating status epilepticus, which is why administration of undiluted doses is of interest. Prior studies have shown safety of IV doses from 1000 mg to 4500 mg; however, assessments of adverse side effects outside IV site reactions have not been studied.

Methods

A retrospective analysis was completed with patients who received 1500 mg doses of undiluted IV LEV. We included patients ≥ 18 years old that received at least 1 dose of IV LEV 1500 mg from January 2018 to February 2021. Study end points included assessment of hemodynamic disturbance (bradycardia [HR less than 50 beats per minute] or hypotension [SBP less than 90 mmHg] within 1 hour or documented infusion reaction within 12 hours of LEV. Descriptive statistics were utilized.

Results

A total 213 doses of 1500 mg of IV LEV were administered to 107 patients. Peripheral lines were used for 85.9% of doses. Approximately half of doses (57) were administered to patients on the general wards, with the remainder in the intensive care unit or emergency department. Two patients (1.9%) experienced bradycardia; however, 1 patient had pre-existing bradycardia. Three patients (3.8%) experienced hypotension; however, those patients were receiving vasopressors prior to the dose. There were no cases of infusion reaction.

Conclusion

Undiluted, rapid administration of IV LEV 1500 mg was well tolerated and safe.

Introduction

Levetiracetam (LEV) is an antiseizure medication (ASM) that is commonly used for chronic and acute management of seizures, including status epilepticus. ¹ It possesses an advantageous side-effect profile compared to most other ASM options. ² Historically, LEV has been given as a slow infusion rate and was diluted before administration. LEV used to be manufactured to an acidic pH, the primary reason for the dilution and slow infusion rate, which could decrease the likelihood of adverse effects. LEV has since been manufactured with a buffer to further neutralize its pH to a more tolerable level. ³ With the acidic formulation, the necessary dilution and slow infusion rate leads to potential delays in patient care which is not ideal when treating acute seizure and status epilepticus. A previous study has shown safety when rapidly infusing undiluted LEV at doses < 1000 mg. ⁴ In addition, very recent studies showed that high doses of LEV could be rapidly infused safely with minimal dilution in doses ranging from 1000 mg to 4500 mg.^5,6 Given the paucity of literature on this topic outside of these studies, this retrospective study aims to further the standard of care regarding the safety and efficacy of rapid administration of LEV in the setting of status epilepticus and to evaluate potential side effects beyond local site reaction.

Methods

Patients from a tertiary care hospital in the Mid-South United States were included in the study if they were ≥ 18 years old and received at least 1 dose of undiluted 1500 mg IV LEV. Patients were excluded if they had a documented prior hypersensitivity to LEV or if they were a pregnant female. Data were collected retrospectively from January 1, 2018 to February 1, 2021. The primary objective was to determine safety and if there were any adverse drug reactions. Adverse drug reactions included bradycardia, hypotension, and infusion reactions. Bradycardia was defined as a heart rate less than 50 beats per minute and hypotension as a systolic blood pressure less than 90 mmHg occurring within 1 hour of IV LEV administration. Data on infusion reactions were collected from nursing documentation within 12 hours of IV LEV administration and included IV site pain, thrombophlebitis, or induration. Interventions in response to these adverse reactions were collected as well. Descriptive statistics were used in the analysis. Institutional Review Board approval was obtained for this project via our institution.

Results

Baseline demographics of included patients are exhibited in Table 1. A total of 213 doses of 1500 mg of IV LEV were administered to 107 patients. Patients had a median age of 55 years (25–75% IQR 40–46), a median weight of 68.2 kg (25–75% IQR 59.1–84.3), and a median length of stay of 2.6 days (25–75% IQR .9–7.3). There were 57 females (53.3%) and 84 patients were African American (78.5%). A peripheral line was used for 183 doses (85.9%). Approximately half of all doses (54.2%) were administered to patients on the general medicine wards, with the remainder in the intensive care unit (ICU) or emergency department (ED). Most patients received a singular dose of IV LEV; however, 20 patients (18.7%) received 2 or more doses. In 74 patients (69.2%), status epilepticus was the admitting diagnosis (Figure 1). There were 66 patients who had a history of seizures with 17 (51.9%) being on LEV previously. Baseline vitals included a median heart rate of 82 (25–75% IQR 71–99) and a median systolic blood pressure of 136 mmHg (25–75% IQR 117–151).

Table 1.

Demographics of Patients and IV LEV Administration.

Variable	Median (25-75% IQR)
Age	55 (40–66)
Weight (kg)	68.2 (59.1–84.3)
Length of stay (days)	2.6 (.9–7.3)
Baseline vitals
Baseline heart rate	82 (71–99)
Baseline systolic blood pressure (mmHg)	136 (117–151)
Variable	Number (%)
Female	57 (53.3)
Race/Ethnicity
African American	84 (78.5)
Caucasian	20 (18.7)
Other	3 (2.8)
Past medical history
Chronic kidney disease	14 (13.1)
Dialysis	4 (3.7)
Cardiovascular disease a	21 (19.6)
Prior seizure history	66 (61.7)
LEV as a home medication	17 (51.9)
Admission diagnosis
Status epilepticus	74 (69.2)
Intracerebral hemorrhage	4 (3.7)
Acute ischemic stroke	6 (5.6)
Subarachnoid hemorrhage	4 (3.7)
Subdural hematoma	0 (0)
Postop from neurosurgical procedure	1 (.9)
Traumatic brain injury	3 (2.8)
Location of 1500 mg IV LEV administration
General ward	58 (54.2)
Intensive care unit	19 (17.8)
Emergency department	30 (28)
Type of line utilized
Peripheral IV	183 (85.9)
Central line	30 (14.1)
Number of doses of 1500 mg IV LEV
Single dose of 1500 mg IV LEV	87 (81.3)
≥2 doses of IV LEV	20 (18.7)

^aCardiovascular disease was defined as any type of heart failure, coronary artery disease, prior myocardial infarction, or valvular disease.

Figure 1.

Distribution of diagnoses requiring IV LEV. This figure depicts the range of diagnoses requiring LEV administration. Out of 107 patients, status epilepticus was the highest proportion of patients requiring LEV.

With regards to adverse events, 2 patients (1.9%) experienced bradycardia. One patient, however, had pre-existing baseline bradycardia after suffering a cardiac arrest. Three patients (3.8%) experienced hypotension. However, all of them were already receiving vasopressors prior to the dose. There were no documented cases of infusion reaction. With respect to patients receiving multiple doses of 1500 mg IV LEV, there were no instances of bradycardia nor infusion reaction. Two of the 3 patients that had hypotension received multiple doses of 1500 mg IV LEV. One patient received 8 doses and the other 5, but as previously noted, there were other causes of the hypotension causing the patients to be receiving pressors prior to the dose of IV LEV.

Discussion

In our retrospective, single center, observational study we found that rapid administration of LEV in doses up to 1500 mg IV was tolerated well by patients. There was only 1 patient that had bradycardia that was not explained by a concomitant medication. Additionally, all 3 patients with documented hypotension had a prior diagnosis explaining the drop in blood pressure and no patients had an infusion site reaction.

There are 3 prior studies that discuss the rapid IV infusion of LEV.^4-6 The first is a retrospective study published in March 2019 that looked at doses of IV LEV ranging from 500 mg to 1000 mg finding that this was safe and well tolerated. Out of the 199 patients and 1626 doses, there were no patients with adverse events, though the only events measured were IV site related. There were also 3 patients who had behavioral side effects; however, this was with multiple doses of IV LEV. ⁴ The second study was another retrospective study with doses up to 2000 mg, with similar results related to IV site reactions. ⁵ A third very recent retrospective cohort looked at rapid IV LEV doses ranging from 1000 mg to 4500 mg. There were 953 patients and 8561 doses, 3674 of which were more than 1000 mg. Of these cases, 2 patients had adverse reactions. Adverse events in this study were also related to IV site problems. In these individuals after replacement of the IV there were no further issues. ⁶

In the 2019 ESETT trial, there was a non-statically significant 5% risk of hypotension with IV LEV specifically in older patients and there were no reported arrythmias in any age group. ¹ Thus far, our study is the only one to assess for hemodynamic adverse events in addition to IV site problems with rapidly administered high dose IV LEV. Our results corroborate the findings of other retrospective studies in the safety and effectiveness of high push dose IV LEV. One of the main reasons that doses of IV LEV >1000 mg are avoided is due to burning during its injection. ³ However, now that LEV is manufactured to be buffered with a more neutral pH, the burning side effects are minimized.^3-6

Our study differs from these prior reports as the patients included in our study are 78.5% African American, which is in parallel with the population the hospital serves. Additionally, we included patients with kidney disease or on dialysis while other studies did not. There are several limitations of our study. Given the impaired level of arousal of some patients due to seizures or post ictal state, there may have been an underreporting of IV site adverse events. We were unable to collect data regarding times from when the order for IV LEV was placed to when it was administered due to constraints within our hospital’s electronic medical record. Due to the retrospective nature of our study, there was also a lack of standardization of nursing documentation when it came to reporting subjective information such as pain or burning sensations from patients. Additionally due to the protocol of our institution, we were unable to assess for doses larger than 1500 mg. Loading doses of up to 3000 mg are given often at our hospital, however, because doses are given in 1500 mg increments, we were unable to accurately collect data on higher doses. We did not collect data on behavioral side effects as these side effects are far delayed after the initial prompt IV administration of bolus LEV doses, which was the main assessment of this study. Further prospective studies are needed to further asses the safety of high dose IV LEV, particularly to standardize documented infusion reaction symptoms felt by patients.

Conclusion

Administration of rapid IV LEV 1500 mg was safe and well tolerated. This study adds to the minimal available literature and can allow for safe rapid administration in emergent situations, such as status epilepticus.

ORCID iDs

Brittany M. Kasturiarachi https://orcid.org/0000-0001-8580-4849

G. Morgan Jones https://orcid.org/0000-0002-3224-1031