# Optimizing anti-seizure medication management in therapeutic plasma exchange: A practical case report

Valentin Coirier, Marie Gallais, Adrien Benard, Mihai Dragos Maliia, Joanna

Bourgine, Bénédicte Franck

► To cite this version:

Valentin Coirier, Marie Gallais, Adrien Benard, Mihai Dragos Maliia, Joanna Bourgine, et al. Optimizing anti-seizure medication management in therapeutic plasma exchange: A practical case report. Transfusion and Apheresis Science, 2025, 64 (5), pp.104239. 10.1016/j.transci.2025.104239. hal-05238307

HAL Id: hal-05238307

https://hal.science/hal-05238307v1

Submitted on 31 Oct 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
<figure><img src="image_2.png" /></figure>

# Optimizing anti-seizure medication management in therapeutic plasma exchange: A practical case report

<figure><img src="image_3.png" /></figure>

Valentin Coirier<sup>a,b,*</sup>, Marie Gallais<sup>a,b</sup>, Adrien Benard<sup>c,d</sup>, Dragos-Mihai Maliia<sup>c,d</sup>, Joanna Bourgine<sup>e</sup>, Bénédicte Franck<sup>f,g</sup>

## ARTICLE INFO

**Keywords:**

Therapeutic plasma exchange

Therapeutic drug monitoring

New onset of refractory status epilepticus (NORSE)

## ABSTRACT

Therapeutic plasma exchange (TPE) is a widely employed procedure for treating several diseases. However, its impact on drug removal is understudied. In critical care settings, the therapeutic window is often narrow but crucial to optimize drug efficacy. This case report details a new onset of refractory status epilepticus, which required the administration of four concomitant anti-seizure medications and the implementation of TPE. We conducted drug monitoring before and after TPE sessions, describing for the first time the removal rate of midazolam and propofol during TPE (low removal rate), and confirming existing data concerning levetiracetam and phenytoin. In critically ill patients, the concomitant use of narrow therapeutic index drugs and plasma exchange requires close drug monitoring.

## 1. Introduction

Therapeutic plasma exchange (TPE) is widely used for the treatment of several diseases [1]. It involves an extracorporeal process wherein a large volume of blood is removed from the patient, subsequently separated by centrifugation or filtration. While the plasma is removed, the remaining blood components return to the patient.

TPE's efficacy is based on two main mechanisms: the removal of pathological substances from the blood and/or the replacement of a deficient plasma component [2]. TPE not only eliminates pathological elements but also affects drug concentrations. It is generally recognized that key factors allowing drug removal during TPE are a low volume of distribution ($Vd < 0.2–0.3 L/kg$), a high plasma protein binding affinity ($>80 %$) [3] and a prolonged half-life [4]. However, limited data regarding drug removal during TPE is available [5]. This aspect can have a crucial impact, such as underexposure and lack of efficacy, especially for drugs with a narrow therapeutic index, like anti-seizure medication (ASM).

We report a case of new-onset refractory status epilepticus (NORSE), necessitating concomitant administration of four ASMs and the implementation of TPE, during which drug monitoring was performed. We describe for the first time the removal of propofol and midazolam during TPE sessions.

## 2. Case description

A 54-year-old woman (height 1.64 m, weight 50 kg), without previous medical history, presented to the Emergency Department for an acute alteration of consciousness. Clinical examination found altered consciousness, with a Glasgow Coma Scale score of 11/15, low-grade fever at 38.2°C, without any other anomalies. The patient was admitted to the Intensive Care Unit (ICU) and mechanically ventilated due to severe neurological impairment. A first lumbar puncture ruled out meningitis, and the initial brain Magnetic Resonance Imaging (MRI) was normal. However, the electroencephalogram showed findings consistent with the onset of encephalitis (periodic discharges

<footnote><sup>a</sup> Intensive Care Unit, Rennes University Hospital, Rennes, France</footnote>

<footnote><sup>b</sup> Faculty of Medecine, University of Rennes, Rennes, France</footnote>

<footnote><sup>c</sup> Neurology Department, Rennes University Hospital, Rennes, France</footnote>

<footnote><sup>d</sup> University of Rennes, INSERM, LTSI-U1099, Rennes 35000, France</footnote>

<footnote><sup>e</sup> Toxicology and Pharmacology Laboratory, Caen University Hospital, Caen, France</footnote>

<footnote><sup>f</sup> Department of Clinical and Biological Pharmacology and Pharmacovigilance, Clinical Investigation Center CIC-P, Rennes 1414, France</footnote>

<footnote><sup>g</sup> University of Rennes, Rennes University Hospital, École des Hautes Études en Santé Publique, IRSET (Institut de Recherche en Santé, Environnement et Travail), UMR S, Rennes 1085, France</footnote>

<footnote>* Correspondence to: Rennes University Hospital, 2, rue Henri Le Guilloux, Rennes 35000, France.</footnote>

<footnote>E-mail address: valentin.coirier@chu-rennes.fr (V. Coirier).</footnote>
predominant in the right hemisphere), without recorded seizures. A few days later, the patient appeared to have a seizure, with a rapid evolution to status epilepticus. A second brain MRI was performed, revealing a compatible aspect with a limbic encephalitis (Fig. 1). An exhaustive etiologic screening was performed, but remained negative. The clinical evolution worsened with NORSE, requiring the use of four different ASMs. At the same time, the first-line treatment for limbic encephalitis was initiated, including corticosteroids and polyvalent immunoglobu-lins. Despite this treatment, clinical deterioration continued and brain MRI showed new inflammatory lesions. Consequently, the decision was made to initiate TPE (Fig. 1), hypothesizing an immunologic trigger. The plasmapheresis technique used was centrifugation, and the device was the Comtec Cell Separator (Fresenius Kabi-61352 Bad Homburg, Ger-many). The venous access used was a double-lumen dialysis catheter. Anticoagulation of the extracorporeal circuit was achieved using acid citrate dextrose solution A, and the replacement fluid was albumin 4 %. TPE was conducted three times a week, totaling 11 sessions. The median session duration was 82 min, with an exchanged volume of 3500 mL (1.3 times the estimated total plasma volume, the same volume for all the sessions).

In this context of NORSE, we questioned the ASM removal during TPE sessions. To optimize the therapeutic management, drug monitoring was performed by determining the ASM plasma concentration just before and just after some of the TPE sessions (left to the clinician's discretion). Cefepime and acyclovir, respectively used to treat ventilator-associated pneumonia and herpetic stomatitis, were also monitored when administered (Fig. 1). All medications were administered through a central venous line.

Infusion was continuous for propofol, midazolam and cefepime, while levetiracetam, acyclovir and phenytoin were administered intermittently (no perfusion during TPE sessions). No dosage adjustments were made between the different TPE sessions. Pharmacokinetic parameters and measured plasma concentrations (pre and post-TPE) for each drug are presented in Table 1.

### 3. Discussion

Despite their widespread use in ICU, the impact of TPE on propofol and midazolam removal has not been previously reported. We expected a low removal rate for these two drugs considering their pharmacokinetic parameters [6] and their continuous administration. This was confirmed by drug monitoring, indicating that a bolus of midazolam or propofol after TPE sessions was unnecessary.

Phenytoin and levetiracetam removal during TPE are documented in case series and reports [7,8]. The variations of concentrations (respectively -23 % and -29 %) we report are in accordance with those already published. Given their intermittent administration and their removal rate, it seems relevant to administer these drugs after TPE sessions.

We had very limited data on cefepime [9] and acyclovir removal, making it difficult to predict the effect of TPE. Continuous administration resulted in minimal removal of cefepime, while acyclovir was surprisingly highly removed [5], thus acyclovir should be administered after the session to ensure its efficacy.

Although the sample size is small and the pharmacokinetic properties of the drugs vary, a lower median variation during the session was observed for drugs administered continuously. Additionally, a high inter-session variability (CV%) was noted, ranging from 42.4 % to 71.9 % for drugs with more than two pre/post-TPE drug monitoring sessions. No correlation with the length of the session was identified.

The strength of our observations lies in being the first to report propofol and midazolam removal during TPE sessions. However, the study has several limitations, primarily the small number of drug dosages. We conducted drug monitoring only immediately before and after the sessions, which limits our ability to observe any post-distribution rebound effect, as previously demonstrated [10].

### 4. Conclusion

Considering the high variability and lack of data, therapeutic drug monitoring should always be performed during TPE sessions to avoid underexposure and inefficacy of the treatments, especially for critically

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Overview of Therapeutic Plasma Exchange Sessions, Drug Administration, and Therapeutic Monitoring During Hospitalization. Second brain MRI: Axial slice of a brainMRI, FLAIR sequence. Bilateral and symmetrical T2 FLAIR hyper intense swelling, primarily affecting the hippocampal regions, insular regions, and basifrontal areas, suggesting a limbic encephalitis as the primary hypothesis. Continuous lines: drugs administered continuously via intravenous infusion. Dashed lines: drugs administered intermittently via intravenous infusion, on a fixed schedule. Red stars: drug monitoring performed (immediately before and immediately after TPE session). ICU: intensive care unit; MRI: magnetic resonance imaging; TPE: therapeutic plasma exchange.</figcaption></figure>
<table><caption>**Table 1**
Drug monitoring just before and just after therapeutic plasma exchange sessions.</caption><thead><tr><th rowspan="2">Drug (number of TPE sessions)</th><th rowspan="2">Vd (L/kg)</th><th rowspan="2">Plasma protein binding (%)</th><th rowspan="2">t<sub>1/2</sub> (hours)</th><th rowspan="2">Modality of infusion</th><th colspan="2">Concentration (mg/L)</th><th rowspan="2">Mean variation (%) (CV%)</th></tr><tr><th>Pre-TPE</th><th>Post-TPE</th></tr></thead><tbody><tr><td rowspan="5">Midazolam (n = 5)</td><td rowspan="5">0.7-1.2</td><td rowspan="5">96-98</td><td rowspan="5">1.5-3.5</td><td rowspan="5">CI</td><td>0.256</td><td>0.268*</td><td>-13.3</td></tr><tr><td>0.239</td><td>0.2</td><td>(54.4)</td></tr><tr><td>0.2</td><td>0.17</td><td></td></tr><tr><td>0.244</td><td>0.199</td><td></td></tr><tr><td>0.143</td><td>0.112</td><td></td></tr><tr><td rowspan="4">Propofol (n = 4)</td><td rowspan="4">18.9</td><td rowspan="4">98-99</td><td rowspan="4">2-14</td><td rowspan="4">CI</td><td>1.9</td><td>1.7</td><td>-12.6</td></tr><tr><td>1.8</td><td>1.4</td><td>(71.9)</td></tr><tr><td>1.9</td><td>1.5</td><td></td></tr><tr><td>1.5</td><td>1.5*</td><td></td></tr><tr><td rowspan="5">Levetiracetam (n = 4)</td><td rowspan="5">0.5-0.7</td><td rowspan="5">&lt; 10</td><td rowspan="5">7</td><td rowspan="5">II</td><td>61.7</td><td>59.0*</td><td>-28.8</td></tr><tr><td>35.7</td><td>19.7</td><td>(42.4)</td></tr><tr><td>34.0</td><td>22.5</td><td></td></tr><tr><td>33.8</td><td>22.9</td><td></td></tr><tr><td>1.5</td><td>1.0</td><td>-22.8</td></tr><tr><td rowspan="4">Phenytoin (n = 5)</td><td rowspan="4">0.4-0.5</td><td rowspan="4">88</td><td rowspan="4">12.0-28.9</td><td rowspan="4">II</td><td>3.0</td><td>1.7</td><td>(65.9)</td></tr><tr><td>2.8</td><td>2.4</td><td></td></tr><tr><td>1.7</td><td>1.2</td><td></td></tr><tr><td>3.2</td><td>3.4</td><td></td></tr><tr><td>Cefepime (n = 1)</td><td>0.26</td><td>20</td><td>2</td><td>CI</td><td>65.0</td><td>60.9</td><td>-6.3</td></tr><tr><td>Acyclovir (n = 2)</td><td>0.69</td><td>10-30</td><td>1.5-3</td><td>II</td><td>1.79</td><td>0.82</td><td>-51.6</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>0.55</td><td>0.28</td><td>(4.9)</td></tr></tbody></table>

Abbreviations: CI: continuous infusion, CV%: inter-sessions mean variability calculation, II: intermittent infusion, t₁/₂: half-life, TPE: therapeutic plasma exchange, Vd: Volume of distribution. *Discordant results could be explained by analytical variability, sampling errors, missing administration information. However, results were included in the calculation of CV%.

In patients. We report for the first time the low removal rate of propofol and midazolam during TPE sessions.

## Funding information

This research received no funding.

## CRediT authorship contribution statement

**Valentin Coirier:** Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Data curation, Conceptualization. **Bénédicte Franck:** Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Joanna Bourgine:** Writing – review & editing, Validation, Investigation, Data curation. **Dragos-Mihai Maliia:** Writing – review & editing, Validation, Investigation. **Adrien Benard:** Writing – review & editing, Validation, Investigation. **Marie Gallais:** Writing – review & editing, Validation, Investigation, Data curation.

## Declaration of Competing Interest

The authors declare no conflict of interest.

## Data availability statement

The data that support the findings of this study are available on

request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

## References

[1] Connelly-Smith L, Alquist CR, Aqui NA, Hofmann JC, Klingel R, et al. Guidelines on the use of therapeutic apheresis in clinical practice - Evidence-Based approach from the writing committee of the American society for apheresis: the ninth special issue. J Clin Apher 2023;38:77-278.

[2] Reeves HM, Winters JL. The mechanisms of action of plasma exchange. Br J Haematol 2014;164:342-51.

[3] Cheng CW, Hendrickson JE, Tormey CA, Sidhu D. Therapeutic plasma exchange and its impact on drug levels: an ACLPS critical review. Am J Clin Pathol 2017;148: 190-8.

[4] Ghannoum M, Bouchard J, Nolin TD, Ouellet G, Roberts DM. Hemoperfusion for the treatment of poisoning: technology, determinants of poison clearance, and application in clinical practice. Semin Dial 2014;27:350-61.

[5] Mahmoud SH, Buhler J, Chu E, Chen SA, Human T. Drug dosing in patients undergoing therapeutic plasma exchange. Neurocrit Care 2021;34:301-11.

[6] Sahinovic MM, Struys M, Absalom AR. Clinical pharmacokinetics and pharmacodynamics of propofol. Clin Pharm 2018;57:1539-58.

[7] White RL, Garnett WR, Allen JH, Kline BJ, Sharp DE. Phenytoin removal during plasma exchange. J Clin Apher 1987;3:147-50.

[8] Hau Man TH, Shek-Kwan CR, On-Kei CA, Lam CPW. Effect of plasmapheresis on serum levels of clobazam, levetiracetam and topiramate. Epilepsy Behav Case Rep 2017;8:66-8.

[9] Ibrahim RB, Liu CY, Cronin SM, Murphy BC, Cha R, et al. Influence of plasma exchange on the disposition of the fourth generation cephalosporin cefepime. J Oncol Pharm Pr 2009 Dec;15:217-22.

[10] Nasca TJ, Huff N, Livengood BH. Phenytoin pharmacokinetics in therapeutic plasmapheresis. J Clin Pharm 1985;25(4):302.