DESCRIPTION
SUBSTANCE CLASS
Carboxylic Acid Derivative |
INTERVENTION CRITERIA
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 |
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 |
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: Vomiting Lethargy/drowsiness Confusion Agitation Tremor Ataxia Racing heart |
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. 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.  |
Monitor: Level of consciousness Heart rate Blood pressure ECG Respiratory rate Blood gas analysis Seizure activity Urea and electrolytes Serum ammonia Serum lactate Full blood count Liver function tests Blood glucose |
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) Hyperammonemia Metabolic acidosis Encephalopathy Hepatotoxicity |
TREATMENT
TREATMENT SUMMARY
Severe toxicity is unlikely in the majority of overdoses. 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. 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.   Patients with chronic valproate toxicity will require referral to a neurologist for dosage adjustment and monitoring of their on-going therapy. |
EMERGENCY STABILIZATION
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.  Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, supplemental dextrose should be administered IV. |
Follow standard protocols for the management of metabolic acidosis.
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Level of consciousness Heart rate Blood pressure ECG Respiratory rate Blood gas analysis Seizure activity Urea and electrolytes Serum ammonia Serum lactate Full blood count Liver function tests Blood glucose |
DECONTAMINATION
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. |
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 CHILD 1 to 2 g/kg orally ADULT 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 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).   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.   CHILD < 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 ADOLESCENT or ADULT 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.  After completion of the procedure the patient should be expected to have additional liquid bowel movements for a period of time. |
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. 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. |
ANTIDOTE(S)
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.  The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia,  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.  Administration of L-carnitine is thought to normalize metabolism and has well established clinical benefit in reversing hyperammonemia in these patients.  It is recommended prophylactically in “at-risk” patients on valproic acid therapy.    |
Decreased level of consciousness Hyperammonemia Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely: Ingestions > 100 mg/kg valproic acid  Hepatotoxicity   |
L-Carnitine Dosage in Acute Valproic Acid Poisoning CHILD and ADULT   IV 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.   |
L-carnitine does not have any absolute contraindications other than known previous hypersensitivity.   |
Seizures are reported, both in patients with or without a prior history of convulsive disorder.   Tachydysrhythmias, hypertension, and hypotension are also noted.  Gastrointestinal upset  and an unpleasant, fishy body odor may occur.   No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.  |
SIGNS AND SYMPTOMS
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.  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.   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.  Delayed cerebral edema may occur though it 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. Pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose. |
Onset/Duration of Symptoms |
Mild Valproate Toxicity | Moderate Valproate Toxicity | Severe Valproate Toxicity | Mild drowsiness Confusion Nausea Vomiting Tachycardia | Moderate to severe drowsiness Agitation Hyperammonemia Hypocalcemia Hypernatremia Thrombocytopenia Hypotension Miosis | Unconsciousness / coma Respiratory depression Metabolic acidosis Elevated creatnine kinase Hepatotoxicity Seizure Encephalopathy Cerebral edema Cardiac or respiratory arrest |
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NZ: 23.May.2022 |