## 2 Materials and Methods  
### Patients and Data Collection  
The study was conducted in the intensive care unit of a tertiary hospital (Latsio Burn Center, Thoriasio General Hospital of Elefisna, Attica, Greece). Fourteen critically ill patients were enrolled in the study and all of them received intravenous (IV) levetiracetam (Keppra(r)) either for prophylaxis or treatment of epilepsy. The study protocol was reviewed by the hospital Scientific Committee and written informed consent was obtained from all patients or their legal representatives before enrolment in the study. The study was conducted in accordance with the International Conference on Harmonization guidelines for good clinical practice and the Declaration of Helsinki, while all patient data were collected and processed in full compliance with the EU General Data Protection Regulation 2016/679 and EU Directive 2016/680 of the European Parliament [32; 33; 34; 35]. Patient data included information on levetiracetam administration and ICU admission, demographics, biochemical parameters (e.g., liver enzymes, urea, albumin), fluid balance (in mL) and organ function expressed by the Sequential Organ Failure Assessment Score (SOFA) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score [36]. From patients' weight and height, the body mass index (BMI) and body surface area (BSA) were also calculated [37]. The SOFA score is used to track the status of an ICU patient and determine the extent of their organ function or rate of failure. In this study, several expressions of this score were calculated, such as SOFA hemodynamic, SOFA liver, SOFA kidneys, and overall SOFA. The APACHE II is calculated within 24 h of a patient's admission to the ICU using various measurements such as heart rate, respiratory rate, blood pH, and hematocrit. Taking all these factors into account, an integer value from 0 to 71 is calculated, with higher values indicating a more severe condition and a higher risk of death. Epileptic activity was also monitored and classified as negative, possible, and positive. The \"positive\" group included patients who had epileptic seizures, while the \"negative\" group included those who had no epileptic activity and levetiracetam was administered for prophylactic reasons only. The \"possible\" category included patients who had a clinical profile of epileptic activity, but this was not verified by electroencephalogram. In this study, particular attention was paid to the role of renal function, as many of the patients in the ICU had impaired renal function. For this reason, various measures of renal function were calculated, such as creatinine clearance over time, Cockcroft-Gault creatinine clearance, and measures of estimated renal function (eGFR) such as MDRD eGFR (Modification of Diet in Renal Disease study group), CKD-EPI eGFR (Chronic Kidney Disease epidemiology collaboration), Jelliffe eGFR in mL/min/1.73 m\({}^{2}\)[38; 39; 40]. Patients in this study were divided into two subgroups according to their renal function; patients with stable renal function (group A) and patients with acute renal impairment (group B) (Table 1). Levetiracetam treatment data included dosing regimen, cause of administration, chronic treatment, and loading dose administration. Levetiracetam was administered diluted in 100 mL N/S 0.9% _w/v_ by IV infusion over 15 min, while the loading dose was administered in 250 mL N/S 0.9% _w/v_ by IV infusion over 30 min. Blood samples for all participants were taken two days after the start of dosing to ascertain whether the serum levels had achieved a steady state. The specific time points for blood collection were determined according to the pharmacokinetics of levetiracetam to obtain as much information as possible. The schedule for blood collection was 0 h (trough level), 20 min, and 3 h after steady-state administration of levetiracetam. The actual blood sampling times were recorded.