Extracorporeal elimination in acute valproate intoxication

Abstract

Severe poisoning with valproate may result in coma and death. The management of valproate intoxication is principally supportive. Valproate is scarcely excreted renally and is mainly protein bound and, therefore, not considered to be amenable for extracorporeal elimination. Despite these unfavourable pharmacokinetic properties, several case reports showed successful treatment of valproate intoxication with haemodialysis and/or haemoperfusion. We describe a male patient (57 years) after ingestion of 64 g of valproate. The patient was successfully treated with haemodialysis for 6 h. Haemodialysis was followed by continuous venovenous haemodiafiltration (CVVH-D) for 18 h to prevent a rebound phenomenon. This report confirms the benefit of haemodialysis in serious valproate overdose. A review of the literature shows that haemodialysis followed by CVVH-D is the treatment of choice in severe valproate intoxication.

BACKGROUND

Since its introduction in 1968, valproate has become the first choice antiepileptic drug for generalised seizure disorders.^1,2 In addition, valproate is currently applied as a mood stabiliser in bipolar disorders, for neuropathic pain, and for the prevention of migraine. With its increasing use, accidental and intentional (auto-)intoxications with valproate have become more common.³ In 2000 in the USA, over 9500 intoxications with valproate were recorded, of which approximately 50% were intentional.⁴ However, the optimal treatment for valproate intoxication is still not clearly defined.

Valproate intoxication generally follows a mild course. Severe poisoning with valproate, however, may result in coma, haemodynamic instability, cerebral oedema, cardiac and respiratory arrest, and, occasionally, death. Severe toxicity has been associated with ingestions of 19–45 g in adults and most adverse outcomes have occurred at peak drug concentrations >450 mg/l (therapeutic range: 40–120 mg/l). Central nervous system depression is the main symptom of valproate intoxication, and is due to the production of the neurotoxic metabolite 2-en-valproate. There is little relation between central nervous effects (depth of coma) and serum valproate values. However, unconsciousness appears to occur only if >200 mg/kg bodyweight has been ingested. Patients with values >850 mg/l uniformly present with coma, 63% of them requiring intubation. Besides central nervous system depression, hypotension, metabolic acidosis, hypernatraemia, hepatotoxicity, and hepatic encephalopathy may all be life threatening. Haemodynamic instability and metabolic acidosis may occur at concentrations >850–1000 mg/l. Hyperammonaemia may occur and result in central nervous system depression, but is typically not life threatening.^3,4

The management of severe valproate intoxication is principally supportive. Absorption of valproate is rapid, usually within 1–4 h after ingestion. Consequently, the window of opportunity for gastrointestinal decontamination is small. However, in cases of ingestion of enteric coated or chronic release preparation, the absorption phase may be substantially delayed and last for up to 24 h. When this is the case, repeated administration of activated charcoal and laxatives may be useful, even after more than 4 h after ingestion. For valproate no specific antidotes are available. Treatment with L-carnitine may enhance detoxification of valproate by ß-oxidation. There is, however, insufficient evidence for routine application of this therapy. Therefore, supportive treatment remains the mainstay of valproate overdose.^3,4

In therapeutic dosages, valproate is mainly eliminated by the liver with an elimination half life of 6–17 h, and only 1% of the dose is excreted in the urine as unchanged drug. Moreover, protein binding is approximately 90% and valproate clearance is minimally affected by haemodialysis. These characteristics indicate that valproate may not be readily amenable to extracorporeal elimination. However, despite these unfavourable pharmacokinetic properties, several case reports showed successful treatment of valproate intoxication with haemodialysis and/or haemoperfusion.^5–15 Two reasons may be responsible for this unexpected success of extracorporeal elimination. First, valproate protein binding is substantially reduced at toxic serum concentrations (>150 mg/l) due to saturation of binding places.⁶ Second, the volume of distribution of valproate is small and limited to the blood volume (0.2 l/kg). Consequently, in serious intoxications with valproate, extracorporeal elimination should be considered.

Although the value of extracorporeal elimination techniques in valproate intoxication is undisputed, it is unknown which technique is most suitable for the elimination of valproate. In some cases a rebound phenomenon has been observed after an initial rapid clearance of the drug, probably due to redistribution. To prevent this rebound, a two phase elimination technique, in which the initial haemodialysis phase is followed by a phase of continuous veno-venous haemodialysis, is postulated as the elimination modus of choice.⁵

The clinical experience with extracorporeal elimination in valproate intoxication remains limited. Therefore, we report a case of a serious valproate intoxication successfully treated with haemodialysis and continuous veno-venous haemodiafiltration (CVVH-D).

CASE PRESENTATION

A male patient, 57 years of age, with a medical history of epilepsy and a previous suicide attempt 12 years earlier, was admitted to the emergency department of our hospital about 1 h after ingestion of 64 g of valproate (80 tablets Depakine enteric coated 300 mg and 80 tablets of Depakine chrono 500 mg) together with 10 units of alcohol.

TREATMENT

Activated charcoal was administered but the patient had vomited immediately after ingestion. At the time of admission the patient was somnolent, although the Glasgow Coma Score (GCS) was still maximal. The patient had teary eyes. Charcoal and sodium sulfate were re-administered, and serum valproate values were determined 4 h after the estimated time of ingestion. The serum ethanol value at 1.5 h after ingestion was 1.6‰. Five hours after ingestion the patient was in deep sleep and could not be aroused, but he did respond to painful stimuli. Ten hours after ingestion a serum valproate value of 966 mg/l 5 h after ingestion was recorded (fig 1). The patient became progressively comatose with a decline in GCS (E1M1V1). A repeat blood sample taken at 12 h after ingestion showed a value of 1069 mg/l. The patient was admitted to the intensive care unit (ICU) for intubation and mechanical ventilation. The patient did not require additional sedation during the admission on the ICU.

Figure 1. Serum concentration of valproate in the patient.

CVVH-D, continuous veno-venous haemodiafiltration; HD, haemodialysis.

Total intestinal (bowel) lavage with a polyethylene glycol-containing solution administered through a nasogastric tube at 250 ml/h was started approximately 12 h after ingestion. Shortly after, haemodialysis for 6 h was initiated, followed by 18 h of CVVH-D. Upon dialysis, the serum valproate values dropped rapidly (fig 1) and the patient remained stable during the procedure.

During dialysis the calculated elimination half life of valproate was 2.3 h during haemodialysis and 7.6 h during CVVH-D. Afterward, the patient’s own terminal half time appeared to be 12.4 h, being in the normal range of 6–17 h.

During the course of dialysis the patient became more awake and could be successfully extubated within 24 h with a maximal GCS. All vital signs normalised and the patient could be discharged from the ICU.

OUTCOME AND FOLLOW-UP

The patient went home on day 9 after admission with no residual deficits.

DISCUSSION

This case confirms the benefit of haemodialysis in serious valproate overdose. In addition, important conclusions can be drawn from the elimination techniques applied in this case and from a thorough review of the currently available literature on extracorporeal elimination in valproate intoxication.

As reviewed by Hicks et al,⁷ haemoperfusion alone showed conflicting results in valproate overdose, while case reports of haemoperfusion combined with haemodialysis were more optimistic. More recently, high flux haemodialysis has been used successfully as monotherapy.^7,8 Haemoperfusion has several important drawbacks limiting its applicability. First, the use of resin or charcoal columns in haemoperfusion is associated with a higher incidence of serious side effects such as thrombocytopenia and disturbances in coagulation. Second, haemoperfusion is both technically and logistically more complicated than haemodialysis, which can be applied in most hospitals. Moreover, haemoperfusion has not been proven to be superior to haemodialysis.⁷ Therefore, we agree with Hicks et al⁷ that haemodialysis is the best available extracorporeal elimination technique for the initial treatment of serious valproate overdose and haemoperfusion should no longer be used.

Although haemodialysis consistently reduces serum valproate levels rapidly, in some case reports a rebound phenomenon has been observed after discontinuation of the dialysis.^5,7–9 A slight increase in valproate levels after termination of haemodialysis suggests that valproate may not follow single compartment kinetics in the toxic range and redistribution from a tissue compartment may occur. In order to prevent such a rebound phenomenon, an additional continuous form of dialysis has been proposed.⁵ Although continuous dialysis is not as efficient as high flux haemodialysis in removing valproate,^5,9 it is haemodynamically milder and may be an excellent technique to clear valproate from its tissue compartments. We and others⁵ successfully applied continuous dialysis after the initial haemodialysis session and did not observe any increase in valproate serum values. Therefore, in valproate overdose, haemodialysis followed by continuous dialysis is efficient, rapid, and safe, and the sequential use appears to be the extracorporeal elimination modus of choice for serious valproate intoxications.

LEARNING POINTS

• Despite its unfavourable pharmacokinetics, valproate in toxic concentrations is amenable to extracorporeal elimination.

• Haemodialysis followed by continuous dialysis appears to be the extracorporeal elimination modus of choice for serious valproate intoxications.