| Optimal Dosing of Levetiracetam for Seizure Prophylaxis in Critically Ill Patients: A Prospective Observational Study |
| Design |
Prospective, observational study N= 205 |
| Objective |
To compare the rates of achievement of target serum levels and new onset seizure (clinical and/or electrographic) among patients who received low (500 mg bid) versus high (750–1,000 mg bid) dose LEV |
| Study Groups |
Low-dose LEV (n= 106) High-dose LEV (n= 99) |
| Inclusion Criteria |
Patients who received prophylactic LEV following traumatic brain injury, intracerebral hemorrhage, spontaneous subarachnoid hemorrhage, or supratentorial neurosurgery between 2019 and 2021 |
| Exclusion Criteria |
Patients with a history of seizure, antiseizure medication use, or renal failure requiring dialysis |
| Methods |
LEV levels were obtained at steady state. The impact of low-dose versus high-dose LEV on the primary outcome of target LEV levels (12–46 μg/mL), and the secondary outcome of clinical and/or electrographic seizure, were assessed using multivariable logistic regression analyses adjusting for age, LEV loading dose, BMI, primary diagnosis and creatinine clearance (CrCl).
The weight-based maintenance dose underwent a sensitivity analysis as a continuous variable in lieu of low-dose versus high-dose dichotomization.
|
| Duration |
July 2019 to August 2021 |
| Outcome Measures |
Primary: Target serum LEV levels (12–46 μg/mL)
Secondary: Multivariable Logistic Regression Results for the Outcome of Target Serum Level for the weight-based maintenance dose.
|
| Baseline Characteristics |
Measure |
500 mg bid (n = 106) |
750 or 1,000 mg bid (n = 99) |
|
|
| Age (median, IQR) |
66 (50–78) |
62 (49–70) |
|
|
| Weight (kg) (median, IQR) |
75 (65–83.9) |
73.3 (63–85.2) |
|
|
| Height (cm) (median, IQR) |
168 (158–175) |
168 (163–173) |
|
|
| BMI (kg/m2) (median, IQR) |
25.8 (23.7–29.1) |
26.3 (22.4–30.1) |
|
|
| Sex (female), n (%) |
46/106 (43%) |
43/99 (43%) |
|
|
| Race, n (%) - White |
50/106 (47.2%) |
40/99 (39.4%) |
|
|
| Race, n (%) - Black |
12/106 (11.3%) |
14/99 (14.1%) |
|
|
| Race, n (%) - Asian |
19/106 (17.9%) |
17/99 (18.2%) |
|
|
| Race, n (%) - Other |
25/106 (23.6%) |
28/99 (28.3%) |
|
|
| Highest level of care, n (%) - Intensive care |
98/106 (93%) |
97/99 (98%) |
|
|
| Principal diagnosis, n (%) - Traumatic brain injury |
54/106 (50.9%) |
43/99 (43.4%) |
|
|
| Principal diagnosis, n (%) - Spontaneous subarachnoid hemorrhage |
24/106 (22.6%) |
23/99 (23.2%) |
|
|
| Principal diagnosis, n (%) - Supratentorial surgery |
20/106 (18.9%) |
23/99 (23.2%) |
|
|
| Principal diagnosis, n (%) - ICH |
8/106 (7.5%) |
10/99 (10.1%) |
|
|
| Admission laboratories (median, IQR) - Creatinine (mg/dL) |
0.85 (0.73–1.07) |
0.92 (0.74–1.24) |
|
|
| Admission laboratories (median, IQR) - Creatinine clearance (mL/min) |
79.4 (59.5–110.1) |
83.9 (61.0–107.4) |
|
|
| Creatinine clearance < 30 mL/min, n (%) |
3/106 (2.8%) |
0 |
|
|
| Augmented creatinine clearance ≥ 130 mL/min, n (%) |
16/106 (15%) |
14/99 (14%) |
|
|
| EEG monitoring, n (%) |
41/106 (39%) |
36/99 (36%) |
|
|
| Days from admission to EEG monitoring (median, IQR) |
4 (1–9) |
2 (2–4) |
|
|
| Hours on EEG (median, IQR) |
48 (30–48) |
48 (48–48) |
|
|
| Length of stay (median, IQR) |
8 (5–18) |
10 (5–21) |
|
|
| Levetiracetam dosage - Loading dose (mg), median (IQR) |
1,000 (500–1,000) |
1,000 (1,000–1,000) |
|
|
| Levetiracetam dosage - Loading dose route IV (vs PO), n (%) |
93/106 (88%) |
91/99 (92%) |
|
|
| Levetiracetam dosage - Maintenance dose (mg/kg/d) (median, IQR) |
13 (12–15) |
25 (19–30) |
|
|
| Levetiracetam dosage - Maintenance dose ≥ 20 mg/kg/d, n (%) |
9/106 (8.5%) |
73/99 (73.7%) |
|
|
| Levetiracetam dosage - Duration of treatment (d) (median, IQR) |
7 (4–10) |
6 (4–9) |
|
|
| Results |
Outcome |
Low-Dose LEV 500 mg bid (n = 106) |
High-Dose LEV 750 or 1,000 mg bid (n = 99) |
p-Value |
|
| Therapeutic serum level (12–46 μg/mL) |
48/106 (45.3%) |
63/99 (63.6%) |
0.008 |
|
| |
Seizure (n= 26) |
No seizure (n= 179) |
|
Odds ratio |
| Maintenance dose (mg/kg/d), median |
18.4 (13.1–25.0) |
15.2 (12.9–23.8) |
0.029 |
0.93 (0.87–0.99) |
| Adverse Events |
Not specifically reported in the study |
| Study Author Conclusions |
Underdosing of LEV was common, with only 54% of patients achieving target serum levels. Higher doses (750–1,000 mg bid) were more than twice as likely to lead to optimal drug levels and reduced the odds of seizure by 68% compared with low-dose regimens (500 mg bid).
|
| Critique |
The study provides valuable insights into the dosing of LEV for seizure prophylaxis in critically ill patients, highlighting the need for higher doses to achieve therapeutic levels. However, the observational design limits the ability to control for all confounding variables, and the lack of continuous EEG monitoring for all patients may have led to an underestimation of seizure rates. Additionally, the study did not systematically track adverse events, which could provide a more comprehensive understanding of the safety profile of higher LEV doses.
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