Continuing Education Activity

Valproate is a commonly prescribed anticonvulsant used in the treatment of seizure and bipolar disorders. Valproate has also been utilized for the treatment of migraine headaches and in the the setting of bipolar disorder. Valproate is an antiepileptic drug with a broad mechanism of action. This CME activity reviews the etiology, epidemiology, mechanism of action, pathophysiology, toxicokinetic, and histopathology of valproate toxicity. This activity will focus on physical examination, diagnosis, management, and prognosis of Valproate toxicity in clinical settings. It also emphasizes patient education and the interprofessional team-based approach necessary for patient-centered care.

Objectives:

• Identify the etiology of valproate toxicity.
• Review the steps in the evaluation of valproate toxicity.
• Outline the management options available for valproate toxicity.
• Describes interprofessional team strategies for improving care coordination and communication to advance and improve outcomes for patients with valproate toxicity.

Introduction

Valproate is a commonly used antiepileptic drug for the treatment of generalized and partial seizures. It is safe for use in both adults and children more than three years of age. It came to the market in 1978, and since then its use has broadened to include the treatment of bipolar and schizoaffective disorders, neuropathic pain, and prophylactic treatment of migraines.[1] Valproate toxicity can occur both accidentally and intentionally. Toxicity can occur with dose adjustments to reach the therapeutic level, in patients with metabolic derangements, with drug-drug interactions, or in attempts to cause self-harm. 

Acute valproate overdose usually presents with CNS depression/encephalopathy, electrolyte abnormalities such as hypernatremia, elevated transaminase levels, hyperammonemia, and hepatoxicity. Patients with a severe overdose of valproate, patients can present with hypotension, tachycardia, respiratory depression, metabolic acidosis, cerebral edema, and valproate-related hyperammonemic encephalopathy which may progress to coma and death, if not treated aggressively. It 

Etiology

Valproate toxicity may occur when increasing the dose of the medication to achieve the desired therapeutic effect. It can also happen when there is a normal total valproate concentration, but the free/unbound drug becomes elevated, as in the case of elderly individuals, in the presence of hypoalbuminemia, pregnancy, renal dysfunction with GFR<50 mL/min/1.73m2, liver disease, and concomitant use of medications that compete for albumin binding sites.[2]

For patients who have bipolar disease or mood disorder, suicidal attempts are possible with an intentional overdose of valproate. However, it is interesting to note that Valproate does not have increasingly significant toxicity when compared to other mood stabilizers.[3]

Epidemiology

According to the American Association of Poison Control Center reports, acute ingestion of valproate has increased from 2717 exposures in 1994 to 8705 in 2005.[4] In more recent times, acute ingestion of valproate cases has stabilized with 3211 cases of valproate ingestion in 2010 and 2996 cases reported in 2018.[5] 

Children having concurrent medical illnesses and who are on chronic valproate therapy are at increased risk of valproate toxicity. In children less than two years, there is a risk of fulminant and fatal hepatotoxicity with valproate exposure.[6]

Pathophysiology

Valproate-induced hepatotoxicity is due to the inhibition of beta-oxidation of fatty acids resulting in mitochondrial injury. Further, valproate decreases tissue carnitine levels, which also results in mitochondrial dysfunction in the hepatocytes resulting in microvesicular steatosis of the liver. Mutation of the gamma polymerase enzyme, which is the primary DNA polymerase inside the mitochondria, makes patients more vulnerable to valproate hepatotoxicity.[7][8] 

Patients with valproate toxicity present with hyperammonemia, anion gap acidosis, metabolic encephalopathy, and hepatotoxicity.[9]

Histopathology

As described above, mitochondrial dysfunction plays an important role in the development of valproate-induced steatohepatitis. Valproate can lead to the buildup of intracellular lipids as well as reactive oxygen species by inhibiting beta-oxidation resulting in mitochondrial dysfunction.[8]

There are various forms of valproate hepatotoxicity, and all show a characteristic pattern of mitochondrial injury, and microscopic histology of the liver reveals microvesicular steatosis with inflammation and cholestasis. Of note, in 5 to 10% of cases, valproate hepatotoxicity can be associated with a rise in ALT levels without an increase in GGT levels. 

Valproate toxicity may also lead to cerebral edema associated with ischemia and herniation.[9] Valproate-induced cerebral edema is due to altered valproate metabolism, which allows the presence of toxic metabolites like 2-EN-VPA in the brain.[10]

Toxicokinetics

Valproate is available in different formulations such as immediate-release, enteric-coated, delayed-release (12 hours), and extended-release (24 hours) forms. It is also available in an intravenous formulation. Divalproex is an extended-release/delayed-release formulation. Therapeutic daily doses range from 15 to 60 mg/kg in children or 500 mg to 2 g in adults.[11]

The liver metabolizes valproate through glucuronide conjugation.[12] Valproate elimination occurs by first-order kinetics(mean half-life 11 hours). It is important to note that half-life can be prolonged to 30 hours due to acute overdose.[13]

Valproate is metabolized by beta and omega oxidation. In valproate toxicity, a greater degree of omega oxidation occurs, which increases the risk of hepatotoxicity, cerebral edema, and hyperammonemia. Metabolites such as 2-propyl-4-pentanoic acid (4-EN-VPA) may mediate hepatotoxicity, and 2-propyl-2-pentanoic acid (2-EN-VPA) may be responsible for cerebral edema, and propionic acid metabolites are responsible for hyperammonemia.[10]

A recent meta-analysis showed that patients with genotype variants such as CYP2C9*3 and CYP2A6*4 affect the concentration of valproate. Hence it is advisable to adjust the dose in the scenario mentioned above to ensure efficacy and prevent toxicity.[14]

Aspirin increases the levels of valproic acid by plasma protein binding competition. Liver disease is associated with decreased albumin concentrations. In hypoalbuminemia, free/unbound valproate concentration increases, although there is normal valproate concentration. An increase in unbound/free valproate correlates with a worse neurological prognosis. So it is crucial to measure unbound valproate concentration in patients having hypoalbuminemia.[15]

History and Physical

Evaluation of a patient with suspected valproate intoxication, collecting the information about the exact time of the ingestion, the formulation of the valproate, the amount ingested, and any other possible coingestants such as OTC medications or alcohol, and any prior psychiatric or medical problems they may have.

Patients with acute ingestion of 200mg/kg or having serum concentrations greater than 180 mg/L often result in central nervous system dysfunction. Neurological manifestations include tremors and agitation. Miosis may be present on pupillary examination. Cerebral edema can be present along with other focal neurological deficits. Valproate-related hyperammonemic encephalopathy may present with confusion, seizures, and lethargy, which may progress to stupor, coma, and death. Vital signs abnormalities such as respiratory depression, hypotension, and tachycardia may occur. Gastrointestinal manifestation includes vomiting, diarrhea, hepatotoxicity, and pancreatitis.[10] Patients may exhibit lethargy, and altered mental status, and with larger serum concentrations of valproate, it can progress to cerebral edema, metabolic acidosis, coma, and death.[16][17]

Dermatohistopathology of valproate toxicity has shown correlations with cases of hypersensitivity vasculitis and psoriasiform eruption. Patients on chronic valproate therapy can present with alopecia due to telogen effluvium evident by diffuse hair loss, thinning, and greying of hair.[18] Valproate is also a potential teratogen, and its exposure during pregnancy correlate with a wide range of congenital malformation, including spina bifida, anencephaly, craniofacial abnormalities, and genitourinary defects.[19]

Evaluation

Therapeutic serum concentrations of valproate usually range from 50 to 100 mg/L. valproic acid concentrations should be obtained at regular intervals (every 2 to 4 hours) until the serum valproate level starts declining. When there is a steady decline in the level, it suggests that a peak serum level has been reached. Patients with serum concentrations greater than 180 mg/dl have a central nervous system (CNS) dysfunction.[20]

Laboratory testing — Routine laboratory evaluation of the poisoned patient should include the following:

A complete blood count (CBC) with differential - thrombocytopenia and decreased in granulocyte counts may be noted.

For women of childbearing age, pregnancy testing is indicated.

Random blood glucose levels are necessary to rule out hypoglycemia as the cause of altered mental status.

Serum AST and ALT levels can assess for hepatotoxicity.

Plasma ammonia levels are necessary for the patient with a risk of encephalopathy.

Serum electrolytes and arterial blood gas analysis may show hypernatremia, metabolic acidosis, and hypocalcemia.  

Screening for other anticonvulsants, aspirin, and acetaminophen should be done as patients may frequently take these drugs with valproate.[20]

Electrocardiography

12 lead EKG should be obtained, and it can show AV conduction block.[21] Sometimes severe valproate toxicity is associated with atrial tachycardia.[22]

Imaging Studies

Head CT is necessary when the patient presents with signs of focal neurological deficits, profound CNS depression, and suspicion of cerebral edema.[18]

Treatment / Management

Therapy for patients with valproate toxicity is mainly supportive and includes initial stabilization and resuscitation. Measures include maintenance of airway, breathing, and circulation. Establish early IV access as intravenous fluid administration for the patients presenting with hypotension. Intravenous boluses of isotonic crystalloid are given in hypotensive patients. Vasopressors may be necessary in severe cases. 

The patient may need admission to the medical intensive care unit for continuous monitoring and treatment.  

Priority is to stabilize all life-threatening conditions. Patients with severe respiratory depression may require endotracheal intubation and mechanical ventilation. Benzodiazepines should be administered if there is a seizure due to valproate toxicity.[23]

Gastrointestinal decontamination is performed with a single activated charcoal single dose if the patient presents within 2 hours of valproate overdose. The usual dose of activated charcoal is 1 g/kg up to 50 kg. If the patient is sedated and is unable to protect the airway, the administration of activated charcoal (AC) should be withheld.

As valproate is available in enteric-coated and extended-release preparations, which have slow absorption, activated charcoal can still be given more than 2 hours after ingestion.[24]

The current literature review suggests that it is prudent to consider the use of L-carnitine for patients presenting with an acute overdose of valproate presenting with altered mental status. L-carnitine dosing is by a loading dose of 100 mg/kg by intravenous route. Treatment with L-carnitine continues with 50 mg/kg every 8 hours. Serum ammonia levels should be simultaneously measured, and when serum ammonia levels start decreasing, L-carnitine therapy can stop.[25] For asymptomatic patients with an acute overdose of valproate, oral carnitine prophylactic dosing is 100 mg/kg/day four times a day. In the pediatric population, evidence from a few case reports shows that carnitine may alter the generation of potentially toxic metabolites, but it may not translate into improved clinical prognosis.[26]

Interestingly, opioid antagonist naloxone in the dose range of 0.8 mg to 2 mg can reverse the central nervous system depression in some cases of valproate poisoning.[27][28] Naloxone may also be useful for chronic valproate intoxication.[29]

Hemodialysis with extracorporeal treatment is indicated for valproate concentration >1300 mg/L (>9000 micromol/L), presence of shock, or cerebral edema. Hemodialysis and hemoperfusion can reduce the elimination half-life of valproate as per the current literature. In one case study, hemodialysis decreased the half-life of valproate from 13 hours before treatment to 1.7 hours after treatment and showed significant clinical improvement within 4 hours of treatment. Intermittent hemodialysis is the preferred extracorporeal elimination technique, although continuous renal replacement therapy (CRRT) is an acceptable alternative if the patient is hemodynamically unstable. Extracorporeal treatment can stop if the serum valproate concentration reduces to 50 to 100 mg/L (350 to 700 micromol/L), and the patient exhibits evidence of clinical improvement as manifested by normal hemodynamic status, improved mental status, and normalizing acid-base and electrolyte balance.[30]

Differential Diagnosis

The most common symptom of valproate toxicity is altered mental status and CNS depression, which can be due to a wide range of conditions. Valproate-induced tremor occurs in about 10% of the patients, which require differentiation from essential tremor and tremors associated with parkinsonism. A comprehensive metabolic panel should assess metabolic derangements, such as hypoglycemia and hypernatremia. As serum ammonia is frequently elevated with valproate poisoning, disorders of urea cycle disorders and hepatic encephalopathy should merit consideration. Suspicion of meningitis should arise when the patient presents with fever, neck stiffness, and altered mental status along with irritability. HSV-1 encephalitis may show temporal lobe involvement, which may be evident on brain imaging. Patients with opioid misuse disorder may present with pinpoint pupil, constipation, and severe respiratory depression, which may reverse with IV naloxone.

Arterial blood gas analysis is essential as other causes of anion gap metabolic acidosis may include uremia, methanol poisoning, diabetic ketoacidosis, acetaminophen toxicity, aspirin toxicity, and lactic acidosis.  Sedative-hypnotics drugs can cause respiratory depression, especially if ingested with opioids. The common causes of cerebral edema include neoplasm, intracranial hemorrhage, hydrocephalus, and traumatic brain injury, which may reveal focal neurological deficits. Physical examination and MRI helps to rule out the causes mentioned above of cerebral edema from Valproate toxicity. Toxicity with other antiepileptic drugs should always be suspected in confirmed cases of epilepsy. 

In summary, differential diagnosis of valproate poisoning is broad, hence a detailed history, physical examination, laboratory evaluation, and cerebral imaging are required.[31]

Prognosis

The prognosis for patients with valproate toxicity will depend on the total amount ingested, the decontamination and elimination strategies, and the supportive care given. Severe ingestions may resolve without any sequelae after aggressive decontamination, elimination, and adequate supportive care. 

In one observational retrospective study involving 316 patients, the prognosis of patients with acute valproate toxicity was good with supportive care. According to multivariate analysis in this study, a coma on the initial presentation was the main poor prognostic factor. Other poor prognostic factors include older age, metabolic derangements, and higher amounts of valproate ingestion.[32]

Complications

Acute valproate toxicity results in dose-related and reversible hepatotoxicity. Stopping the drug therapy usually results in normalization of liver function abnormalities, but idiosyncratic fulminant hepatic failure and death have been reported with valproate toxicity.[33][34]

Liver transplant in children with valproate-induced acute hepatic failure has decreased survival rates compared to liver transplant from other causes of drug-induced liver injury.[35]

Cerebral edema may lead to herniation, prolonged CNS depression, and coma.[13][10]

Valproate-related hyperammonemic encephalopathy can lead to confusion, lethargy, and increased seizure frequency. If valproate toxicity is untreated, it can progress to stupor, coma, and death.[36][37]

Consultations

A poison control center should be consulted when the diagnosis is unclear, or the patient is critically ill.  

All patients with intentional valproate overdose require consultation with a psychiatrist.

Early nephrologist consultation is recommended when the patient has either cerebral edema, presence of shock, or serum valproate concentration>1300 mg/L for hemodialysis according to recommendations by extracorporeal treatments in poisoning(EXTRIP) workgroup guidelines.[30]

Deterrence and Patient Education

On discharge, the patient should receive counsel that liver problems can happen with valproate overdose, which can be fatal. Parents need to know that children under two years are at higher risk of deadly liver problems.[35]

Pregnant ladies should understand that valproate may cause severe birth defects, including spina bifida and neurodevelopmental disorders if taken during pregnancy, and hence it is prudent to use birth control to prevent pregnancy while on valproate.[19]

Parents/caregivers should also understand that there is an increased risk of liver failure in patients with a mitochondrial disorder like Alpers–Huttenlocher syndrome.[35]

The patient should also be counseled regarding the risk of pancreatitis with long-term therapy and hence patient should call the clinician or emergency department immediately if he/she develops symptoms such as acute abdominal pain, nausea, vomiting, and fever.[38]

Following discharge, patients should receive clear instructions on drug dosage, frequency, and route of administration, as well as potential drug interactions.

Enhancing Healthcare Team Outcomes

Valproate toxicity requires excellent interprofessional team coordination between physicians, resident doctors, nurses, emergency medical technicians/paramedics, pathologists, radiologists, hospital pharmacists, and medical toxicologists. Patients can present to the emergency department with impaired hemodynamics and CNS depression. Rapid triage and resuscitation by an emergency physician are critical for initial stabilization. Consultation with the radiologist is vital to identify cerebral edema. As the patient undergoes triage in the ICU in severe cases of poisoning, critical care nursing is of paramount importance for hemodynamic monitoring and overall care of the patient. 

Critical care physician supervision is necessary for the care of intubated patients with severe valproate toxicity. The hospital pharmacist should assist with medication reconciliation and provide accurate dosing for carnitine(intravenous L-carnitine of 100 mg/kg once, followed by infusions of 50 mg/kg (to a maximum of 3 g per dose) every 8 hours till serum ammonia levels are decreasing[25] [Level IIIa], activated charcoal and naloxone. Consultation with nephrology may be required as extracorporeal treatment is recommended in the presence of shock, valproate concentration > 1300 mg/L, and the presence of cerebral edema according to systematic review and recommendations from the EXTRIP workgroup guidelines.[30] [Level IIIa]

Mental health professional consultation is crucial in cases of intentional overdose. Medical students may provide a vital role in the review of the medical chart and patient education. The night float team/nocturnist should receive a face-to-face handoff with all the important information regarding the case. As depicted above, there are multiple health care providers involved in the care of the patient with acute valproate toxicity, and hence excellent and prompt communication is mandatory for improving patient outcomes and reducing morbidity and mortality. The benefits of teamwork are that it leads to improved coordination of care, reduces provider burnout rates, and ultimately helps to achieve better patient outcomes.[39] 

In summary, the interprofessional team approach using evidence-based medicine and patient-centered care correlates with reduced utilization of health care services and better patient outcomes.[40] [Level I]