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Sodium Valproate

Sodium Valproate
15.Aug.2022-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 for:
- Ingestions greater than 50 mg/kg
- Symptomatic cases
- Exposures with intent to self-harm
Decontamination, if appropriate, and medical observation at an emergency department is recommended for:
- Ingestions greater than 100 mg/kg

Acute On Chronic

Medical assessment and observation at an emergency department is recommended for:
- Ingestions 50 mg/kg greater than the patients usual single therapeutic dose
- Symptomatic cases
- Exposures with intent to self-harm
Decontamination, if appropriate, and medical observation at an emergency department is recommended for:
- Ingestions 100 mg/kg greater than the patients usual single therapeutic dose is ingested


Medical assessment and observation is recommended for:
 - Any symptomatic chronic ingestion

Observation Period

Observation at Home

If the patient does not require medical observation they can be observed at home for 12 hours in the care of a reliable observer.
The patient should be medically assessed if any symptoms develop, including:
Racing heart

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, they may be:
Discharged into the care of a reliable observer, or
Referred for psychological assessment if the overdose or exposure was with intent of self-harm
If the patient is symptomatic on presentation, or develops symptoms during the initial observation period, 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 > 100 mg/kg.
Serum concentrations should be taken on presentation and repeated at 2 to 3 hourly intervals initially and 4 to 6 hourly intervals later (to help identify the time of peak concentration and to ensure that a downward trend is observed)[1][2][3]
In particular, patients ingesting enteric coated formulations of valproic acid, or large numbers of tablets/capsules, may have slowed absorption or form concretions in the GI tract. Absorption may be delayed and prolonged. Hence, serial serum valproic acid estimations may be useful to ascertain on-going absorption and guide the need for further GI decontamination and extracorporeal elimination.[3]
Click here to link to toxic serum concentrations


Level of consciousness
Heart rate
Blood pressure
Respiratory rate
Blood gas analysis
Seizure activity
Urea and electrolytes
Serum ammonia
Serum lactate
Full blood count
Liver function tests
Blood glucose

Admission Criteria

Admission to a closely monitored environment is recommended for when:
400 mg/kg or more is ingested
Serum concentration is greater than 6,250 umol/L (900 mg/L) valproic acid
Following symptoms occur 
Coma or respiratory depression requiring mechanical ventilation
Recurrent seizures
Following conditions are present
Severe electrolyte disturbances (e.g. marked hypernatremia)
Metabolic acidosis



Severe toxicity is unlikely in the majority of overdoses.[4] 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 may be warranted for ingestions over 100 mg/kg. Whole bowel irrigation may be a useful adjunct in the treatment of overdoses of enteric coated formulations or patients with rising concentrations despite activated charcoal; pharmacobezoars are possible in these circumstances.
There are no proven antidotes for valproate capable of immediately reversing its toxic effects, however, L-carnitine may be considered an adjunct to standard management.[5][6][7][8]Multiple dose activated charcoal[9][10] and hemodialysis may be useful in severe toxicity.[11][12] Valproic acid concentrations should be regularly monitored.[3]
Further treatment is primarily symptomatic and supportive. CNS depression is a common manifestation of toxicity requiring treatment. Treatment of encephalopathy, seizures, hypotension, electrolyte disturbances, thrombocytopenia, metabolic acidosis, and delayed cerebral edema may sometimes be required following large to massive overdoses. Ammonia concentrations should be checked if encephalopathy is suspected. Hepatotoxicity and pancreatitis are uncommon with overdose, but can occur even with regular therapeutic doses and may be fatal.[13][14][15]
Patients with chronic valproate toxicity will require referral to a neurologist for dosage adjustment and monitoring of their on-going therapy.
Emergency Stabilization
Enhanced Elimination
Supportive Care
Fluid and electrolytes


Ensure Adequate Cardiopulmonary Function

Endotracheal intubation may be 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 possible but uncommon with valproate overdose.
Administer a benzodiazepine as first-line treatment to patients with seizure activity.[16]
Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, supplemental dextrose should be administered IV.
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
Heart rate
Blood pressure
Respiratory rate
Blood gas analysis
Seizure activity
Urea and electrolytes
Serum ammonia
Serum lactate
Full blood count
Liver function tests
Blood glucose



Single Dose Activated Charcoal

Decontamination with activated charcoal is recommended for ingestions over 100 mg/kg.
CNS depression is a likely consequence of significant overdose. Gastrointestinal decontamination should be undertaken with appropriate airway protection in those who are CNS depressed.[4]
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 4 hours previously.
Single dose activated charcoal[17]
1 to 2 g/kg orally
50 to 100 g orally

Nasogastric Administration

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.

Whole Bowel Irrigation

Whole bowel irrigation may be a useful adjunct in the treatment of overdoses of enteric coated formulations or patients with rising concentrations despite activated charcoal.
Whole Bowel Irrigation Procedure
When performed optimally, whole bowel irrigation is a labor intensive task that is more likely to be successful with 1:1 nursing care and can take 4 to 6 hours to complete. Use of a nasogastric (NG) tube is recommended over oral administration as it can be difficult for patients to drink the appropriate amount of irrigation fluid over several hours.
Before commencing ensure the airway is adequately protected, the NG tube is confirmed to be in the stomach, and there is no ileus or intestinal obstruction. The patient should be in an upright position with easy access to a commode (or use a rectal tube).[18][19]
The only irrigant recommended is an iso-osmotic polyethylene glycol electrolyte solution (e.g Macrogol 3350, PEG 3350) approved for GI cleansing and administered at the following rates until the rectal effluent is clear.[18][19]
< 9 months:
There is limited evidence for use in this age group, consultation with a medical toxicologist is advised
9 months to 6 years:
500 mL/hour (or 25 mL/kg/hour) via NG tube
6 to 12 years:
1,000 mL/hour (or 25 mL/kg/hour) via NG tube
1,500 to 2,000 mL/hour via NG tube
To achieve desired infusion rates it may be helpful to start at a slower rate and increase as tolerated over the first 10 to 15 minutes. Enteral feeding pumps may not be able to achieve target rates for adults even on the “flush” setting (if considering use of an enteral feeding pump check the device manual to see what rates can be achieved). A gravity infusion, i.e. hanging the irrigant solution bag to gravity, will typically be able to achieve a rate up to 2,000 mL/hour via NG tube.
Monitor the patient for abdominal distension or vomiting during the procedure. Pre-treatment with antiemetics can be considered. If vomiting occurs, and ileus or obstruction are not suspected, decrease the infusion rate by 50% for 30 to 60 minutes then attempt to increase back to the full rate.[18]
After completion of the procedure the patient should be expected to have additional liquid bowel movements for a period of time.[18]

Exclude Bezoar

While bezoar formation is unlikely following most cases of valproate overdose, the possibility should be considered with the ingestion of enteric-coated or modified-release formulations or in situations where high numbers of tablets/capsule are ingested. Valproate tablets are not radiopaque and are unlikely to be seen on plain x-ray imaging.
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.[20]
Investigation for the presence of a tablet mass in the upper GI tract may be of benefit in the patient with life-threatening toxicity.
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 can be impossible to remove without laparotomy.


There Are No Antidotes For This Substance

No clinically established antidotes capable of immediately reversing toxic effects exist for the treatment of valproic acid overdose. However, L-carnitine and naloxone have both been used in a number of cases with varying results.


Evidence supporting clinical efficacy and safety of L-carnitine in acute valproic acid poisoning is limited.[5] The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia,[21] a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Hypocarnitemia may favor the production of toxic metabolites, and contribute to the development of hyperammonemia.[11] Administration of L-carnitine is thought to normalize metabolism and has well established clinical benefit in reversing hyperammonemia in these patients.[22] It is recommended prophylactically in “at-risk” patients on valproic acid therapy.[8][23][24]
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.[5][21][25] There are also anecdotal reports of reversal of hyperammonemia in acute poisoning.[6][8][26][27] L-carnitine does not appear to have any direct effect on neurological toxicity.[25]
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.[5][7][8]


L-carnitine administration is indicated in patients with:[5][7][8][25][28][29]
Decreased level of consciousness
Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely:
Ingestions > 100 mg/kg valproic acid[5]
Serum valproic acid concentrations > 3,128 umol/L (> 450 mg/L)[5][7][30]

Dose and Administration

The recommended L-carnitine dose for acute valproic acid poisoning is higher than that used for chronic, supratherapeutic poisoning or mild hypocarnitemia.[5][6][7][21][24][26][28] L-carnitine infusion may be required for up to 3 to 4 days.[5][26]
L-Carnitine Dosage in Acute Valproic Acid Poisoning
CHILD and ADULT[5][7]
Loading dose:
100 mg/kg
Doses given as an infusion over 30 minutes
Maximum dose 3 g (up to 6 g has been given)
Maintenance dose:
50 mg/kg every 8 hours or 15 mg/kg every 4 hours
Doses given as an infusion over 30 minutes
Maximum single dose 3 g
End Point:
Ammonia concentrations decreasing, patient demonstrates clinical improvement, or significant adverse effects occur


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.[31][32]


L-carnitine does not have any absolute contraindications other than known previous hypersensitivity.[31][32]

Adverse Effects

Seizures are reported, both in patients with or without a prior history of convulsive disorder.[31][32] Tachydysrhythmias, hypertension, and hypotension are also noted.[5] Gastrointestinal upset[32] and an unpleasant, fishy body odor may occur.[25][28] No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.[29]


Naloxone has been used anecdotally in a small number of cases to reverse valproate-induced CNS depression.[33][34][35][36][37][38][39] This appears to have been more effective with minimally elevated serum concentrations,[39][40][41] with other reports showing no effect with much higher concentrations.[42][43][44] Any effect may be due to reversal of valproate blockade of GABA cellular uptake or reversal of valproate-induced release of endogenous opioids.[39][40][45]


Sodium valproate is rapidly metabolized to valproic acid in vivo.
Common clinical symptoms of valproic acid toxicity vary in severity, depending on the ingested dose, from mild confusion and drowsiness to deep coma and rarely, death.
With ingestions less than 200 mg/kg, effects are generally mild or the patient may remain asymptomatic.[4][46][47] Ingestions from 200 to 400 mg/kg are likely to develop varying degress of decreased consciousness (lethargy, sedation, ataxia). Additionally, gastrointestinal disturbances, tachycardia, hyperammonemia, hypothermia, and rarely hepatic or renal toxicity may develop. Significant CNS depression is likely, with multi-organ involvement as the dose increases.[48][49][50]
Massive overdoses (typically > 800 mg/kg) can result in serious CNS and respiratory depression, hypotension, and metabolic acidosis. Severe hyperammonemic encephalopathy, cerebral edema, and clinically significant thrombocytopenia may develop; hypernatremia, hypocalcemia, and other electrolyte disturbances may be severe and prolonged.[27][51][52]Delayed cerebral edema may occur though it is not common.[53][54] Death is rare, and usually results from cardiac or respiratory arrest.[55]
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are at increased risk of developing hyperammonemic encephalopathy.[56][57] Pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose.[58]

Onset/Duration of Symptoms

Symptoms would usually be expected to develop within 1 to 6 hours of ingestion with most standard preparations.[36][59][53][55][60][61][62][63] Delayed toxicity may occur with ingestion of sustained release or enteric-coated formulations,[2][52][64] or with the prodrug valpromide,[1] with CNS depression developing as late as 8 hours post-ingestion. Ingestion of high numbers of tablets/capsules may also be associated with delayed or prolonged absorption. Metabolic disturbances usually present early, and may be severe and prolonged. The development of cerebral edema is generally delayed, presenting 2 to 3 days or more post-ingestion, and is associated with a higher mortality.[59][65]
Depending on the severity, the duration of intoxication can range from 24 hours to 7 days or longer.[48][66][55][61][63][67]

Severity of Poisoning

Mild Valproate ToxicityModerate Valproate ToxicitySevere Valproate Toxicity
Mild drowsiness
Moderate to severe drowsiness
Unconsciousness / coma
Respiratory depression
Metabolic acidosis
Elevated creatnine kinase
Cerebral edema
Cardiac or respiratory arrest


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