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Sodium Valproate

Sodium Valproate
30.May.2017-Expires: 7 days - Do not archive



Sodium Valproate


Carboxylic Acid Derivative


Intervention Level


Child and Adult

Medical assessment and observation at an emergency department is recommended in any of the following situations:
- 50 mg/kg or more is ingested
- Symptomatic cases
- Intentional ingestions (psychiatric follow-up)
Decontamination is recommended in any of the following situations:
- 400 mg/kg or more is ingested
- The dose is unknown, but likely significant

Acute On Chronic

Medical assessment and observation at an emergency department is recommended in any of the following situations:
- 50 mg/kg more than the patients usual single therapeutic dose is ingested
- Symptomatic cases
- Intentional ingestions (psychiatric follow-up)
Decontamination is recommended in any of the following situations:
- 400 mg/kg more than the patients usual single therapeutic dose is ingested
- The dose is unknown, but likely significant


Medical assessment and observation is recommended:
 - For any symptomatic chronic ingestion

Observation Period

Observation at Home

If the exposure does not meet the intervention level and the patient is asymptomatic, they can be observed at home in the care of a reliable observer. The patient should be observed for 6 hours following ingestion of a standard preparation or for 24 hours if a sustained release formulation has been ingested.
The patient should be medically assessed if any symptoms develop, including:

Medical Observation

If the patient’s ingested dose is above the intervention criteria:
- Observe for development of symptoms for a minimum period of 6 hours when a standard-release preparation has been ingested
- Observe for development of symptoms for a minimum period of 12 hours when an enteric-coated or sustained-release preparation has been ingested
If the patient remains asymptomatic throughout the observation period, and any necessary decontamination and investigations have been carried out:
- Discharge into the care of a reliable observer, or
- Refer for psychiatric assessment (if the overdose was intentional)
If the patient is symptomatic on presentation they should be observed until there has been resolution of signs of valproate toxicity and serum concentrations have fallen into the therapeutic range.



Valproic acid serum concentrations should be measured following ingestion of immediate- and sustained release-preparations when the suspected dose is > 200 mg/kg.
Serum concentrations should be taken on presentation and repeated at 3 to 4 hour intervals (to identify the onset of peak concentrations and ensure that the serum concentrations are falling)[1][2][3]
In particular, patients ingesting enteric coated formulations of valproic acid may have slowed absorption or form concretions in the GI tract. Absorption may be delayed and prolonged. Hence, serial serum valproate estimations may be useful to ascertain ongoing absorption and guide the need for further GI decontamination and extracorporeal elimination.
Click here to link to toxic serum levels


Level of consciousness
Respiratory rate
Oxygen saturations
Heart rate
Blood pressure
Seizure activity
Arterial blood gases
Blood glucose
Urea and electrolytes

Admission Criteria

Hospital admission is recommended when:
- >400 mg/kg or more is ingested
- Serum concentration is greater than 5,908 umol/L (850 mg/L) valproic acid
- Following symptoms occur 
Any decreased level of consciousness
Respiratory depression
Recurrent seizures
- Following conditions are present
Electrolyte disturbances (hypernatremia)
Metabolic acidosis



Severe toxicity is unlikely in the majority of overdoses. However, emergency stabilization may occasionally be required following exposure to massive amounts of valproate, when treatment of cardio-respiratory arrest, seizures, or metabolic acidosis may be necessary.
Decontamination with activated charcoal is recommended for ingestions over 400 mg/kg sodium valproate.
There are no proven antidotes for valproic acid intoxication, although L-carnitine may be considered an adjunct to standard management.[4][5] Multiple dose activated charcoal and hemodialysis may be useful in severe toxicity.[6] Valproic acid concentrations should be monitored.
Acute treatment is primarily symptomatic and supportive, focussing mainly on CNS and respiratory depression. Treatment of encephalopathy, seizures, hypotension, electrolyte disturbances, thrombocytopenia, metabolic acidosis, bone marrow suppression, and hypothermia may sometimes be required following large to massive overdoses. Hepatotoxicity and pancreatitis are uncommon with overdose, but do occur with therapeutic doses and may be fatal. Delayed cerebral edema may occur. Ammonia concentrations should be checked if encephalopathy is suspected.
Patients with chronic valproate toxicity will require referral to their a neurologist for dosage adjustment and monitoring of their ongoing therapy.
Emergency Stabilization
Enhanced Elimination
Supportive Care
Fluid and electrolytes


Ensure Adequate Cardiopulmonary Function

Endotracheal intubation maybe required for airway protection and adequate ventilation of the obtunded patient following overdose. Ensure that the patient is well perfused and hemodynamically stable.
Immediately establish secure intravenous access.


Seizures are uncommon with valproate overdose.
Most toxic seizures are short-lived and often do not require intervention.[7]
Administer a benzodiazepine as first-line treatment to patients with seizure activity.[7]
Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, 50% dextrose should be administered IV (preceded by thiamine in adults).
If seizure activity continues or if there is need for maintenance dosing proceed to further supportive care of toxic seizure.

Metabolic Acidosis

Follow standard protocols for the management of metabolic acidosis.

Emergency Monitoring

Level of consciousness
Respiratory rate
Heart rate
Blood pressure
Seizure activity
Acid-base balance



Single Dose Activated Charcoal

Decontamination with activated charcoal is recommended for ingestions over 400 mg/kg sodium valproate.
CNS depression is a likely consequence of significant overdose. Gastrointestinal decontamination should be undertaken with appropriate airway protection.
Administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a solid formulation (e.g. tablet or capsule) up to 2 hours previously.
Single dose activated charcoal[8]
1 to 2 g/kg orally
50 to 100 g orally

Nasogastric Intubation

Nasogastric instillation of activated charcoal is not recommended unless the ingestion is considered potentially severely toxic. If endotracheal intubation is otherwise required, activated charcoal can be administered following intubation, however, intubation should not be performed solely for the purpose of then administering charcoal.

Exclude Bezoar

While bezoar formation is unlikely following valproate overdose, the possibility should be considered with the ingestion of enteric-coated or modified-release formulations.
Suspect a bezoar or tablet concretion where serum valproate concentration remains persistently elevated or plateaued despite apparently adequate GI decontamination.
Pharmacobezoars (drug concretions) may occur following an ingested overdose of various drugs and, particularly, modified release (e.g. sustained release) or enteric-coated preparations. Such masses may significantly extend or increase the duration of toxicity.[9]
It is recommended that significant overdoses with these compounds be managed with whole-bowel irrigation.[10]
Investigation for the presence of a tablet mass in the upper GI tract may be of benefit in the patient with life-threatening toxicity, but negative imaging studies do not exclude the presence of a bezoar.
Bezoars may be detected by:
- Gastroscopy (can only view stomach and duodenum and impractical if charcoal has been administered as the bezoar may be hidden)
- Abdominal CT scanning with oral contrast
- Plain X-ray examination (but only for radio-opaque concretions)
- Ultrasound examination
If found, the risk and practicality of removal should be weighed against use of supportive care with or without the addition of whole bowel irrigation.
If the bezoar is located in the stomach or duodenum, removal may be attempted endoscopically. Bezoars in the small intestine are inherently difficult to localize and impossible to remove without laparotomy.


There Are No Antidotes For This Substance

No clinically established antidotes exist for the treatment of valproic acid overdose. However, naloxone and L-carnitine have both been used in a number of cases with varying results.
Naloxone has been used successfully in a small number of cases to reverse valproate-induced CNS depression[11][12][13][14][15][16]This appears to have been more effective in patients with minimally elevated serum concentrations,[17][18]with other reports showing no effect in patients with much higher concentrations.[19][20][21]Any effect may be due to reversal of valproate blockade of GABA cellular uptake or reversal of valproate-induced release of endogenous opioids.[17][22]


Evidence supporting clinical efficacy and safety of L-carnitine in acute valproic acid poisoning is limited.[4] The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia,[23] a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Administration of L-carnitine is thought to normalize metabolism[24]  and has well established clinical benefit in reversing hyperammonemia in these patients. It is strongly recommended prophylactically in “at-risk” patients on valproic acid therapy.[25][26]
In acute poisoning there is some, albeit scant, evidence that valproic acid metabolism is similarly inhibited and that administration of L-carnitine similarly normalizes metabolism.[23][27][4] There are also anecdotal reports of reversal of hyperammonemia in acute poisoning.[28][29][30] L-carnitine does not appear to have any effect on neurological toxicity.[27]
L-carnitine may be considered in acute valproic acid poisoning as an adjunct to standard management where hyperammonemia or decreased level of consciousness is present.[4][5]


L-carnitine administration is indicated in patients with:
Decreased level of consciousness[4][5]
Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely:
Ingestions > 100 mg/kg valproic  acid[4]
Serum valproic acid concentrations > 3,128 umol/L (> 450 mg/L)[4][5][33]

Dose and Administration

Note that the recommended L-carnitine dose for acute valproic acid poisoning is higher[4][5][28][29][23] than that used for chronic, supratherapeutic poisoning[31][26][5] or mild hypocarnitemia. Case reports indicate that L-carnitine infusion may be required for up to 3 to 4 days.[4][29]
L-Carnitine Dosage in Acute Valproic Acid Poisoning
Loading dose:
100 mg/kg (bolus over 2 to 3 minutes or infusion over 15 to 30 minutes)[4][5]
Maximum dose 3 g[4](up to 6 g has been given)[5]
Maintenance dose:
50 mg/kg every 8 hours[4] or 15 mg/kg every 4 hours[5]
Doses given either as bolus over 2 to 3 minutes or infusion over 15 to 30 minutes[4][5]
End Point:
Ammonia levels decreasing, patient demonstrates clinical improvement, or significant adverse effects occur.[4][5]


Seizures have occurred in patients taking L-carnitine therapeutically; caution is recommended in patients with underlying seizure disorder. Adequate hydration and a good renal output must be maintained as there is potential for accumulation of toxic metabolites of L-carnitine (trimethylamine and trimethylamine-N-oxide) in patients with renal impairment.[34][35]


L-carnitine does not have any contraindications.[34][35]

Adverse Effects

Seizures are reported, both in patients with or without a prior history of convulsive disorder.[34][35] Tachydysrhythmias, hypertension, and hypotension are also noted.[4] Gastrointestinal upset[35] and an unpleasant, fishy body odor may occur.[27][31] No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.[32]


Sodium valproate is rapidly metabolized to valproic acid in vivo.
CNS depression, ranging from drowsiness to coma, is the most frequent sign after valproic acid overdose; with ingestions less than 200 mg/kg asymptomatic or displaying mild drowsiness and ataxia only. Ingestions from 200 to 400 mg/kg are likely to present varying levels of consciousness. Significant CNS depression is likely with multi-organ involvement as dose increases between 400 and 1,000 mg/kg. Massive overdoses (> 1,000 mg/kg) can result in serious CNS and respiratory depression, hypotension, metabolic acidosis, and bone marrow depression. Severe hyperammonemic encephalopathy, cerebral edema, and clinically significant thrombocytopenia may develop; hypernatremia, hypoglycemia, hypocalcemia and other electrolyte disturbances may be severe and prolonged.[36] Delayed cerebral edema may occur though is not common. Death is rare, and usually results from cardiac or respiratory arrest.
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are at increased risk of developing hyperammonemic encephalopathy. This may occur with therapeutic dosing.
Hepatotoxicity, pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose.
There is a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients starting carbamazepine therapy.[37]

Onset/Duration of Symptoms

Symptoms would usually be expected to develop within four hours of ingestion with most standard preparations of valproate. Delayed toxicity may occur with ingestion of sustained release or enteric-coated formulations, with CNS depression occurring as long as 8 to 13 hours post-ingestion.[38][39]
Metabolic disturbances usually present early, and may be severe and prolonged. The development of cerebral edema may also be delayed, presenting two to three days or more post-ingestion. Bone marrow suppression may present three to five days after a massive overdose, and usually resolves spontaneously a few days later.

Severity of Poisoning

Mild Valproate ToxicityModerate Valproate ToxicitySevere Valproate Toxicity
Mild drowsiness
Increased drowsiness
Electrolyte disturbances
Unconsciousness / coma
Cerebral edema
Respiratory depression
Respiratory or metabolic acidosis
Cardiac or respiratory arrest


Adverse Effects

Adverse effects in patients taking valproate drugs therapeutically are not uncommon, and may also occur in overdose. Some effects such as increases in hepatic enzymes, bone marrow suppression, sedation or ataxia may be misleading, suggesting a higher degree of toxicity following overdose than is present.
There are also some serious adverse effects that occur at therapeutic doses which may occur in overdose. These include fatal hepatotoxicity such as toxic cholestatic hepatitis and hepatocellular necrosis,[25][40]pancreatitis,[41]and severe hyperammonemic encephalopathy.[42][43]
Hepatotoxicity, and rarely hepatic failure, occur most commonly in the first few months of treatment. Young children with multiple medical problems, on multiple antiepileptic agents are at highest risk of fatal hepatotoxicity. Fatalities due to pancreatitis have also occurred.[40][44][45][46]
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, may develop hyperammonemic encephalopathy following initiation of valproate therapy at normal doses.[47]


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