Neither Therapeutic Plasma Exchange nor High-Flux Hemodialysis Enhances the Removal of Chlorprothixene in Case of Intoxication despite a Drop in Plasma Levels: A Case Report

Abstract

Introduction

Chlorprothixene is a typical antipsychotic, primarily used in the treatment of psychotic disorders. Overdose may result in severe cardiovascular and central nervous system toxicity. Evidence on the effectiveness of extracorporeal elimination is scarce.

Case Presentation

A 19-year-old female ingested 5 g of chlorprothixene in a suicide attempt. Upon admission to the intensive care unit, she was awake, responsive, and oriented. Initial management included 50 g of activated charcoal. As doses of >2 g chlorprothixene can cause severe intoxication and death, attempts to enhance drug elimination by extracorporeal therapy were undertaken. Therapeutic plasma exchange (TPE) was initiated approximately 3 h after admission, exchanging 5,096 mL of plasma with albumin solution and FFP over 3 h 10 min. This was followed by a 10 h 10 min prolonged intermittent kidney replacement therapy (PIKRT). Serial blood, apheresis, and dialyzate samples were collected to quantify drug removal. Both procedures were well tolerated. The patient remained clinically stable and was transferred to a psychiatric facility 24 h post-admission.

Conclusion

Although chlorprothixene plasma levels decreased, the amount of chlorprothixene removed by TPE and PIKRT was negligible, classifying the drug as “not dialyzable” per EXTRIP criteria. Given the limited clinical evidence and the pharmacokinetic properties of chlorprothixene, TPE cannot be recommended for the management of chlorprothixene overdose and should not be regarded as a standard treatment option. According to the available literature, this is the first description of chlorprothixene intoxication managed with both TPE and high-flux hemodialysis, highlighting the limited extracorporeal removal of this drug.

Introduction

Drug intoxication is a challenging emergency in clinical practice, requiring rapid action and effective treatment. Extracorporeal treatments can contribute to the removal of toxins and enhance secondary drug elimination for some compounds. Depending on the physicochemical and pharmacokinetic characteristics of the drug, hemodialysis, hemoperfusion, hemofiltration, and therapeutic plasma exchange (TPE) may be effective treatments. In general, the primary goal is to remove the majority of the substance or its metabolites from the body as quickly as possible [1].

Unlike hemodialysis, TPE can eliminate large molecules, drugs with high plasma protein binding as well as lipophilic drugs. Another advantage is that by exchanging all plasma components, inflammatory mediators can also be eliminated [2]. The procedure quickly reduces plasma concentration, making it particularly useful in emergency situations.

Chlorprothixene is a typical antipsychotic drug of the thioxanthene class, primarily used in the treatment of psychotic disorders, agitation, and insomnia [3]. It undergoes extensive hepatic metabolism [4] and, at therapeutic doses, exhibits very high plasma protein binding (>99%) [5] and a large volume of distribution (VOD) (15.5 L/kg) [6], which explains its long duration of action as well as its limited dialyzability. However, in case of overdose, the pharmacokinetics of a drug might be altered the so-called toxicokinetics. For instance, saturation of plasma protein binding or altered tissue distribution can modify the effective VOD and, thereby, influence the expected effectiveness of TPE [7]. According to the available literature, this is the first reported case of chlorprothixene intoxication treated with a combination of TPE and hemodialysis.

The CARE Checklist has been completed by the authors for this case report and is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000551514).

Case Presentation

A 19-year-old woman with a BMI of 45.2 kg/m² was admitted to the hospital after ingestion of 5 g (100 × 50 mg tablets) of chlorprothixene in attempted suicide. Seven days prior, she had been treated after swallowing razor blades as part of her borderline personality disorder.

Upon arrival at the intensive care unit (ICU), the patient was awake, responsive, and oriented to time, location, and situation. She was partially agitated and reported that she had not vomited since taking the tablets. She was already on a regular chlorprothixene regimen before intoxication with a total dose of 150 mg administered in divided doses.

Initial Presentation

After the admission to the ICU, the patient showed mild hypothermia and changing pupillomotor function. Her ECG showed sinus tachycardia with a rate of 107 bpm, and a QTc of 427 ms. Her mild hypoxemia (pO₂ 49.7 mm Hg) 3 h after admission was managed with 2–4 L/min of oxygen via nasal cannula. The laboratory results are shown in Table 1.

Table 1.

Laboratory results of the 19-year-old patient at the admission to the ICU to the hospital day 1

Parameters	Admission day	Hospital day 1
Hematology
Leukocytes (3.98–10.04), 103/μL	8.4	9.8
Erythrocytes (3.93–5.22), 106/μL	4.16	4.34
Hemoglobin (11.2–15.7), g/dL	11.1 (−)	11.3
Hematocrit (34.1–44.9), %	33.4 (−)	34.8
Thrombocytes (150–370), 103/μL	308	240
Clinical chemistry
CRP (<5.0), mg/L	10.4 (+)	6.2 (+)
Sodium (136–145), mmol/L	137	140
Potassium (3.4–4.5), mmol/L	3.86	3.76
Calcium (2.15–2.50), mmol/L	2.31	2.07
Urea (17–48), mg/dL	20	6 (−)
Creatinine (0.51–0.95), mg/dL	0.89	0.53
eGFR (CKD-Epi), mL/min/1.73 m2	>60	>60
Total bilirubin (<1.20), mg/dL	0.4	0.9
ALT (GPT) (<33), U/L	92 (+)	26
AST (GOT) (10.35), U/L	56 (+)	19
GGT (5–36), U/L	42 (+)	11
LDH (135–214), U/L	310 (+)	106 (−)
CK (<170), U/L	162	45
Glucose (74–106), mg/dL	128 (+)	105
Coagulation (citrate plasma)
Quick (77–116), %	88	50 (−)
INR	1.07	1.51
PTT (25–38), s	27	63 (+)

Management and Treatments

As part of the initial management, the patient received 50 g of activated charcoal via a nasogastric tube. This was administered after admission to the ICU to prevent further gastrointestinal absorption of the drug.

Given the young patient’s massive overdose, the aim to prevent further liver injury, and the pharmacokinetic consideration that chlorprothixene is highly protein bound (>99%) but also has a large VOD, hemodialysis was expected to have only minimal impact on drug clearance, and TPE was, therefore, initiated as an individualized, last-resort intervention. Thus, TPE started approximately 3 h after admission and lasted for 3 h and 10 min. The procedure was performed as a centrifugal TPE using the Spectra Optia^® system exchanging 5,096 mL plasma (calculated plasma volume 4,597 mL) against a mixture of FFP and albumin solution using citrate as anticoagulant.

Immediately following TPE, the patient underwent prolonged intermittent kidney replacement therapy, which lasted for 10 h and 10 min. Hemodialysis was performed using a Genius^® HD system using a Rexeed-25A dialyzer (Asahi Kasei Medical) with a 2.5 m² surface area at a blood flow rate of 250 mL/min and dialyzate flow of 125 mL/min.

Follow-Up and Clinical Outcomes

The patient survived the intoxication. Both TPE and hemodialysis were well tolerated, with no adverse or unexpected events reported during or after the procedure. The following day, the patient remained in a hemodynamically and clinically stable condition and was transferred to a psychiatric facility 24 h after the admission.

Blood Sampling

Samples were taken at defined time points from the patient’s serum, apheresate (waste bag), ultrafiltrate, and dialyzate. The samples were immediately centrifuged for 10 min at 2,000 g and 23°C after collection. The serum was stored at −80°C until it was transported to the MVZ Medizinisches Labor Bremen GmbH (Bremen, Germany). Quantitative analysis was performed using liquid chromatography-mass spectrometry.

Results

The amount of drug eliminated by TPE (Q_PE) was calculated as 2,226 µg. Using a VD of 15.5 L/kg and the pre-TPE concentration, the total body store was calculated as 2,399 mg, resulting in a fractional drug elimination (f_e) of 0.093%. The plasma clearance due to TPE (CL_PE) was calculated to be 0.97 L/h, with an estimated TPE-related elimination half-life (t_1/2PE) of 1.05 h, based on an AUC_PE of 2,292 µg·h/L.

Immediately following TPE, the patient underwent hemodialysis. Serum concentrations before and after dialysis showed a minimal reduction (245 µg/L before dialysis vs. 179 µg/L after dialysis). Chlorprothixene concentrations in both dialyzate and ultrafiltrate were below the quantification limit (<5 µg/L), indicating negligible removal. Overall, the additional decline in serum concentrations over the course of dialysis was modest, possibly representing redistribution rather than extracorporeal clearance. Figure 1 represents the serum concentration over time and the visual impact TPE and hemodialysis had on plasma concentration.

Fig. 1.

Serum concentration of chlorprothixene over time in a 19-year-old female patient in the treatment period. Blue shaded: drop in serum concentration due to TPE; green shaded: drop in serum concentration due to PIKRT. Serum levels declined rapidly after TPE, followed by a slower decrease during dialysis.

Discussion

These findings indicate that TPE yielded a reduction in plasma chlorprothixene levels, whereas hemodialysis had minimal effect. Based on the total ingested amount, the total removed chlorprothixene would be qualified by the EXTRIP as “not dialyzable” [8]. The low effectiveness of both extracorporeal methods can be attributed to the drug’s pharmacokinetic profile, particularly its large VOD and high lipophilicity, limiting both plasma-based and diffusion-based elimination. In addition, chlorprothixene has a low oral bioavailability of approximately 17%, which indicates an extensive first-pass metabolism [9]. Hepatic biotransformation via CYP2D6 is considered the main elimination pathway [4], and our patient’s markedly elevated liver enzymes (AST, ALT, and GGT; Table 1) within 2 h of ingestion support early and pronounced hepatic involvement. It is, therefore, likely that a substantial proportion of the ingested dose was metabolized in the liver before it could appear in the systemic circulation, which further reduces the fraction accessible to extracorporeal removal.

Literature suggests a therapeutic range for chlorprothixene in the plasma is 0.02–0.3 mg/L [10]. In our patient, the maximum level was 1.29 mg/L, i.e., more than 4 times above the upper therapeutic level. Of note, several fatalities have been reported with concentrations in postmortem blood ranging from 0.1 to 7.0 mg/L [11]. In a single case where chlorprothixene was considered the sole cause of death, the postmortem level was 0.9 mg/kg, i.e., even lower than in our patient [12]. In 6 cases in which chlorprothixene was considered a contributing cause of death, the levels ranged between 0.43 and 0.91 mg/kg [12]. These data underline the severity of the intoxication and the importance of appropriate therapy.

However, since TPE only eliminated 0.093% of the total estimated amount of chlorprothixene and considering the dominant role of hepatic metabolism, the survival of our patient cannot be causally attributed to extracorporeal therapies alone. Its effect on the overall burden of the drug was relatively minimal. Given the paucity of clinical evidence and the pharmacokinetic characteristics of chlorprothixene, no recommendation can currently be made in favor of TPE as a specific treatment for chlorprothixene overdose, and TPE should not be regarded as a standard therapeutic modality in this setting. At most, TPE may be considered on an individualized, adjunctive basis in life-threatening intoxications with highly protein-bound psychotropic agents when conventional supportive measures have been exhausted.

Statement of Ethics

This case report describes a single patient and does not constitute a clinical study as defined by local legislation and institutional requirements. Therefore, approval by an ethics committee was not required. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflict of Interest Statement

Prof. Jan T. Kielstein was a member of the journal’s Editorial Board at the time of submission. The other authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

M.N. and J.T.K. were responsible for the conception, design, and drafting of the manuscript. S.S., B.A., and C.H.H. contributed to data collection. All authors have read and approved the final manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data supporting the findings of this case report are included in the article itself. Additional references are cited in the reference list. Further inquiries can be directed to the corresponding authors.