The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based clinical recommendations on the use of extracorporeal treatment (ECTR) in various poisonings. Here we will review their guidance in the case of anti-epileptic drug (AED) toxicities. We don’t see this too often as Nephrologists. However as these drugs are now in widespread use for many other indications such as neuropathic pain, bipolar disorder and migraine, AED toxicity may occur more frequently and we should familiarize ourselves with our role in its management. Being anti-epileptic drugs, neurological manifestations are common in intoxication, however differences in protein binding and volume of distribution make decisions about extracoporeal removal quite different for them

Carbamazepine

Carbamazepine (CBZ) has a similar structure to tricyclic anti-depressants. CBZ has a molecular weight of 236 Da and is highly bound to both albumin and alpha-1-acid glycoprotein (70 – 80%). It has a slow rate of dissolution, which results in erratic and incomplete absorption. It is highly lipophilic and distributes rapidly and extensively albeit with a relatively small volume of distribution.

CBZ is metabolized in the liver by the cytochrome P450 system. CBZ induces its own metabolism with chronic use; this auto-induction occurs relatively early in therapy, is dose-dependent, and explains why carbamazepine-naïve patients usually exhibit more toxic symptoms than those who use it therapeutically. Carbamazepine’ s half-life with initial dosing is reported to be 25 – 65 h, which decreases to 12 – 17 h with repeated or continued dosing. In overdose, much longer apparent half-lives are reported.

The therapeutic concentration range is 4 – 12 mg/L (17 – 51 μmol/L); significant toxicity usually occurs over 40 mg/L (169 μmol/L). Neurologic symptoms including movement disorders, altered mental status, and seizures. Respiratory depression is common in severe overdose. Cardiovascular effects include sinus tachycardia, hypotension, myocardial depression, and cardiac conduction disturbances. Death has been reported due to refractory cardiovascular toxicity. In one large cohort of 427 patients, the overall mortality was 13%.

Most cases of toxicity can be successfully managed with appropriate supportive care including airway protection with endotracheal intubation, treatment of seizures with benzodiazepines, and correction of hypotension with fluid challenges and vasopressors if needed. Hypertonic sodium bicarbonate can be used if evidence of sodium channel blockade is present on the electrocardiography. Multiple-dose activated charcoal (MDAC) increases elimination and improves clinical outcome in patients with overdose, and is recommended for patients with life-threatening ingestions.

In the cases of severe carbamazepine poisoning, ECTR is recommended if multiple seizures refractory to treatment occur or if life-threatening dysrhythmias occur. ECTR is suggested if prolonged coma and/or respiratory depression requiring mechanical ventilation is present or expected. Extracorporeal modalities may also be employed if significant toxicity persists, especially if CBZ concentrations rise or remain elevated, despite multiple-dose activated charcoal (MDAC) and supportive measures. Intermittent HD is the preferred ECTR in CBZ poisoning but intermittent hemoperfusion or continuous renal replacement therapy may be used if HD unavailable. MDAC should be continued during ECTR.

Take home messages:

• Significant toxicity including altered mental status, seizures, and cardiac dysrhythmias usually occur over 40 mg/L (169 μmol/L).
• ECTR recommended if refractory seizures or life-threatening dysrhythmias develop; suggested if prolonged coma or respiratory depression occur.

Phenytoin

Phenytoin (PHY) is a hydantoin derivative. It has a molecular mass of 252 Da and binds extensively to plasma proteins (90%), a percentage that remains unchanged after overdose, but decreases to 75% to 80% in patients with kidney failure, hypoalbuminemia, or CYP450 2C9 genetic polymorphism. The unbound or free form is responsible for its clinical and toxicologic effects. The reported time to peak plasma concentrations in therapeutic dosing is 1.5 to 3 hours for standard formulations and 4 to 12 hours for extended-release formulations. Peak plasma concentrations have been observed up to 96 hours after ingestion in the overdose setting.

Phenytoin has a volume of distribution of 0.6 to 0.8 L/kg and is predominantly metabolized by the CYP enzyme system to inactive metabolites. The drug exhibits Michaelis-Menten kinetics; as such, increased doses may produce a larger than expected increase in plasma concentrations and prolonged elimination. In over-dose, the apparent elimination half-life increases; in one case, it was reported to be as long as 103 hours. This explains why massive phenytoin ingestions may lead to prolonged toxicity and extended hospital stays.

Oral overdose is characterized by cerebellar and vestibular effects, including multidirectional nystagmus, dizziness, nausea, vomiting, and ataxia. Severe overdose may result in coma and marked respiratory depression. Death or irreversible injury following phenytoin poisoning is infrequent. Intra-venous overdose produces similar systemic effects but cardiotoxicity, including hypotension, bradycardia, arrhythmias, and even asystole, can occur. These side effects relate to the diluent (propylene glycol) rather than phenytoin itself.

Management of patients with phenytoin toxicity is largely supportive, including airway protection and correction of hypotension with intravenous fluids. Gastrointestinal decontamination (eg, single-dose activated charcoal) should be given if the patient presents shortly after ingestion and has no contraindications, although there is no evidence that this alters the clinical course.

However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning. This is defined by the presence or expectation of prolonged coma or prolonged incapacitating ataxia. The group did not recommend using suspected doses or serum phenytoin concentration as a guide. Intermittent hemodialysis is the modality of choice with intermittent hemoperfusion an acceptable alternative if this is unavailable.

Take home messages:

• Overdose is characterized by cerebellar effects, coma, respiratory depression or cardiotoxicity.
• Consider dialysis only if prolonged coma or disabling ataxia present.

Valproate

Intentional and unintentional valproate (VPA) overdoses are common. In 2013, the American Association of Poison Control Centers ’ National Poison Data System recorded a total of 7776 cases including VPA, of which 2923 were single exposures, including 65 cases of major toxicity and 2 deaths.

VPA has a small molecular mass of 144 Da. The time to reach peak plasma concentrations is 1 – 4 h during normal therapeutic dosing, but may be prolonged to more than 7 h in overdose. VPA has a small volume of distribution and exhibits saturable plasma protein binding. The corresponding increase in the active fraction of free (unbound) drug likely leads to greater clinical toxicity.

The drug is primarily metabolized in the liver by glucuronide conjugation and to a lesser extent by mitochondrial β-oxidation and cytosolic ω-oxidation. Only a small proportion of VPA is excreted unchanged in the urine. Its elimination half-life is approximately 12 h at therapeutic concentrations, but increases to more than 30 h in overdose.

Concentrations between 50 and 100 mg/L (350 – 700μmol/L) are considered therapeutic. Ataxia, sedation, and lethargy commonly occur in mild poisoning with ingestions around 200 mg/kg. At ingestions of 400 mg/kg or more, severe VPA poisoning is associated with coma and respiratory depression requiring mechanical ventilation, cerebral edema, hemodynamic instability, and shock that may lead to a fatal outcome. Laboratory abnormalities reported during severe poisoning include hypernatremia, hypocalcemia, thrombocytopenia, evidence of impaired mitochondrial function (i.e., metabolic acidosis, hyperlactatemia), and hyperammonemia which is thought to play a role in the pathogenesis of cerebral edema.

Initial attention should be directed to the need for airway protection and cardiovascular stabilization. Patients presenting with a recent VPA ingestion may benefit from gastrointestinal decontamination with single-dose activated charcoal. The use of multiple-dose activated charcoal (MDAC) in the treatment of VPA poisoning is not currently recommended.

L-carnitine is proposed as an antidote for VPA poisoning. It is postulated that L-carnitine depletion may impair the mitochondrial transportation and β-oxidation of VPA, favor the production of toxic metabolites, and contribute to the development of hyperammonemia. L-carnitine supplementation may increase mitochondrial β-oxidation and thus limit cytosolic ω-oxidation and the production of toxic metabolites. L-carnitine is commonly recommended in patients with VPA toxicity and hyperammonemic encephalopathy. However, evidence supporting the use of L-carnitine as an antidote for VPA poisoning is limited.

Acute VPA toxicity should be differentiated from valproate-induced hyperammonemic encephalopathy, which may exhibit clinical characteristics similar to mild VPA overdose but is characterized by elevated ammonia concentrations in the setting of VPA concentrations within or near the therapeutic range.

Because of its small molecular mass, low endogenous clearance, and small volume of distribution, VPA would appear to be readily removable by most ECTRs were it not for its high protein binding at therapeutic concentration. However, in situations such as uremia and overdose, the protein binding sites for VPA decrease or saturate, thereby increasing the fraction of unbound drug, rendering it more amenable to extracorporeal removal. ECTR is advised with severe valproate (VPA) poisoning. Its use is recommended if the concentration is > 1300 mg/L (9000 μ mol/L), if shock is present, or if cerebral edema is present. ECTR is suggested if any of the following is present: If the [VPA] is > 900 mg/L (6250 μ mol/L), if coma or respiratory depression requiring mechanical ventilation is present, if acute hyperammonemia is present or if pH is < 7.10. It can be ceased in the event of clinical improvement or if [VPA] is between 50 and 100 mg/L (350 – 700 μ mol/L). Intermittent hemodialysis is again preferred in cases of VPA poisoning but both intermittent hemoperfusion and CRRT can be used if this is unavailable.

Take home messages:

• At ingestions of 400 mg/kg or more, severe VPA poisoning is associated with coma and respiratory depression, cerebral edema, hemodynamic instability, and shock.
• ECTR is recommended if the concentration is >1300mg/L (9000 μ mol/L), if shock or cerebral edema is present.
• You should also consider ECTR if the concentration is >900mg/L (6250 μ mol/L), if coma or respiratory depression, if acute hyperammonemia is present or if pH is < 7.10.

Click here for EXTRIP Reference : Carbamazepine, Phenytoin, Valproate

About the author

I'm an Irish Renal Fellow currently working in University Hospital Limerick.